645 results on '"intrinsic excitability"'
Search Results
2. CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny
- Author
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Assendorp, Nora, Fossati, Matteo, Libé-Philippot, Baptiste, Christopoulou, Eirini, Depp, Marine, Rapone, Roberta, Dingli, Florent, Loew, Damarys, Vanderhaeghen, Pierre, and Charrier, Cécile
- Published
- 2024
- Full Text
- View/download PDF
3. The enigmatic HCN channels: A cellular neurophysiology perspective.
- Author
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Mishra, Poonam and Narayanan, Rishikesh
- Abstract
What physiological role does a slow hyperpolarization‐activated ion channel with mixed cation selectivity play in the fast world of neuronal action potentials that are driven by depolarization? That puzzling question has piqued the curiosity of physiology enthusiasts about the hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, which are widely expressed across the body and especially in neurons. In this review, we emphasize the need to assess HCN channels from the perspective of how they respond to time‐varying signals, while also accounting for their interactions with other co‐expressing channels and receptors. First, we illustrate how the unique structural and functional characteristics of HCN channels allow them to mediate a slow negative feedback loop in the neurons that they express in. We present the several physiological implications of this negative feedback loop to neuronal response characteristics including neuronal gain, voltage sag and rebound, temporal summation, membrane potential resonance, inductive phase lead, spike triggered average, and coincidence detection. Next, we argue that the overall impact of HCN channels on neuronal physiology critically relies on their interactions with other co‐expressing channels and receptors. Interactions with other channels allow HCN channels to mediate intrinsic oscillations, earning them the "pacemaker channel" moniker, and to regulate spike frequency adaptation, plateau potentials, neurotransmitter release from presynaptic terminals, and spike initiation at the axonal initial segment. We also explore the impact of spatially non‐homogeneous subcellular distributions of HCN channels in different neuronal subtypes and their interactions with other channels and receptors. Finally, we discuss how plasticity in HCN channels is widely prevalent and can mediate different encoding, homeostatic, and neuroprotective functions in a neuron. In summary, we argue that HCN channels form an important class of channels that mediate a diversity of neuronal functions owing to their unique gating kinetics that made them a puzzle in the first place. [ABSTRACT FROM AUTHOR]
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- 2025
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- View/download PDF
4. Mechanisms of glutamate receptors hypofunction dependent synaptic transmission impairment in the hippocampus of schizophrenia susceptibility gene Opcml-deficient mouse model
- Author
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Xiaoxuan Sun, Hu Meng, Tianlan Lu, Weihua Yue, Dai Zhang, Lifang Wang, and Jun Li
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Hippocampus ,Schizophrenia ,Intrinsic excitability ,Glutamatergic neurotransmission ,AMPA/NMDA ratio ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Schizophrenia is a severe psychiatric disorder with high heritability, characterized by positive and negative symptoms as well as cognitive abnormalities. Dysfunction in glutamate synapse is strongly implicated in the pathophysiology of schizophrenia. However, the precise role of the perturbed glutamatergic system in contributing to the cognitive abnormalities of schizophrenia at the synaptic level remains largely unknown. Although our previous work found that Opcml promotes spine maturation and Opcml-deficient mice exhibit schizophrenia-related cognitive impairments, the synaptic mechanism remains unclear. By using whole-cell patch clamp recording, we found that decreased neuronal excitability and alterations in intrinsic membrane properties of CA1 PNs in Opcml-deficient mice. Furthermore, Opcml deficiency leads to impaired glutamatergic transmission in hippocampus, which is closely related to postsynaptic AMPA/NMDA receptors dysfunction, resulting in the disturbances of E/I balance. Additionally, we found that the aripiprazole which we used to ameliorate abnormal cognitive behaviors also rescued the impaired glutamatergic transmission in Opcml-deficient mice. These findings will help to understand the synaptic mechanism in schizophrenia pathogenesis, providing insights into schizophrenia therapeutics with glutamatergic disruption.
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- 2024
- Full Text
- View/download PDF
5. Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.
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Tian, Guilian, Bartas, Katrina, Hui, May, Chen, Lingxuan, Vasquez, Jose J., Azouz, Ghalia, Derdeyn, Pieter, Manville, Rían W., Ho, Erick L., Fang, Amanda S., Li, Yuan, Tyler, Isabella, Setola, Vincent, Aoto, Jason, Abbott, Geoffrey W., and Beier, Kevin T.
- Subjects
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GLOBUS pallidus , *CARNOSIC acid , *DOPAMINE agents , *BASAL ganglia , *RABIES virus , *POTASSIUM channels , *DOPAMINE receptors - Abstract
The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder. [Display omitted] • Globus pallidus is part of a 4-node circuit controlling cocaine sensitivity • KCNQ3 and KCNQ5 expression is reduced following cocaine administration • Carnosic acid inhibits GPePV cells through activating KCNQ3/5 heteromers • Carnosic acid reduces cocaine reward, sensitization, and self-administration Tian et al. demonstrate that the activity of cells in the mouse globus pallidus can predict neurophysiological and behavioral responses to cocaine. This discovery leads to the identification of carnosic acid, derived from the ancient medicinal plant rosemary, as a potential therapeutic that reduces cocaine reward and self-administration. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
6. Mechanisms of glutamate receptors hypofunction dependent synaptic transmission impairment in the hippocampus of schizophrenia susceptibility gene Opcml-deficient mouse model.
- Author
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Sun, Xiaoxuan, Meng, Hu, Lu, Tianlan, Yue, Weihua, Zhang, Dai, Wang, Lifang, and Li, Jun
- Subjects
COGNITION disorders ,METHYL aspartate receptors ,NEURAL transmission ,MENTAL illness ,SCHIZOPHRENIA ,GLUTAMATE receptors - Abstract
Schizophrenia is a severe psychiatric disorder with high heritability, characterized by positive and negative symptoms as well as cognitive abnormalities. Dysfunction in glutamate synapse is strongly implicated in the pathophysiology of schizophrenia. However, the precise role of the perturbed glutamatergic system in contributing to the cognitive abnormalities of schizophrenia at the synaptic level remains largely unknown. Although our previous work found that Opcml promotes spine maturation and Opcml-deficient mice exhibit schizophrenia-related cognitive impairments, the synaptic mechanism remains unclear. By using whole-cell patch clamp recording, we found that decreased neuronal excitability and alterations in intrinsic membrane properties of CA1 PNs in Opcml-deficient mice. Furthermore, Opcml deficiency leads to impaired glutamatergic transmission in hippocampus, which is closely related to postsynaptic AMPA/NMDA receptors dysfunction, resulting in the disturbances of E/I balance. Additionally, we found that the aripiprazole which we used to ameliorate abnormal cognitive behaviors also rescued the impaired glutamatergic transmission in Opcml-deficient mice. These findings will help to understand the synaptic mechanism in schizophrenia pathogenesis, providing insights into schizophrenia therapeutics with glutamatergic disruption. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
7. Neuropathic pain has sex‐specific effects on oxycodone‐seeking and non‐drug‐seeking ensemble neurons in the dorsomedial prefrontal cortex of mice.
- Author
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Sarka, Bailey C., Liu, Shuai, Banerjee, Anjishnu, Stucky, Cheryl L., Liu, Qing‐song, and Olsen, Christopher M.
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CHRONIC pain , *SUBSTANCE abuse relapse , *PREFRONTAL cortex , *OPIOID abuse , *NERVOUS system injuries - Abstract
Approximately 50 million Americans suffer from chronic pain, and nearly a quarter of chronic pain patients have reported misusing opioid prescriptions. Repeated drug seeking is associated with reactivation of an ensemble of neurons sparsely scattered throughout the dorsomedial prefrontal cortex (dmPFC). Prior research has demonstrated that chronic pain increases intrinsic excitability of dmPFC neurons, which may increase the likelihood of reactivation during drug seeking. We tested the hypothesis that chronic pain would increase oxycodone‐seeking behaviour and that the pain state would differentially increase intrinsic excitability in dmPFC drug‐seeking ensemble neurons. TetTag mice self‐administered intravenous oxycodone. After 7 days of forced abstinence, a drug‐seeking session was performed, and the ensemble was tagged. Mice received spared nerve injury (SNI) to induce chronic pain during the period between the first and second seeking session. Following the second seeking session, we performed electrophysiology on individual neurons within the dmPFC to assess intrinsic excitability of the drug‐seeking ensemble and non‐ensemble neurons. SNI had no impact on sucrose seeking or intrinsic excitability of dmPFC neurons from these mice. In females, SNI increased oxycodone seeking and intrinsic excitability of non‐ensemble neurons. In males, SNI had no impact on oxycodone seeking or neuron excitability. Data from females are consistent with clinical reports that chronic pain can promote drug craving and relapse and support the hypothesis that chronic pain itself may lead to neuroadaptations which promote opioid seeking. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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8. Electrophysiological properties of melanin-concentrating hormone neuron subpopulations defined by anatomical localization and CART expression
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Rafiat Damilola Adekunle, Mohammed Sohel Chowdhury, Lisa Z. Fang, and Michiru Hirasawa
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melanin-concentrating hormone (MCH) ,intrinsic excitability ,cocaine and amphetamine-regulated transcript (CART) ,hypothalamus ,zona incerta ,H-current ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionMelanin-concentrating hormone (MCH) neurons are essential regulators of energy and glucose homeostasis, sleep–wake behaviors, motivation, learning and memory. These neurons are anatomically distributed across the medial (MH) and lateral hypothalamus (LH), and the adjacent zona incerta (ZI), which may represent functional subgroups with distinct connectivity with different brain regions. Furthermore, MCH neurons can be classified according to co-expression of neuropeptides, such as cocaine and amphetamine- regulated transcript (CART).MethodsTo identify functional similarities and differences of MCH subpopulations, we characterized their intrinsic electrophysiological properties using whole cell current clamp recording on acute brain slices from male and female mice.ResultsMCH neurons were classified into subgroups according to their anatomical localization in three MCH-rich brain areas: MH, LH and ZI. Among the three brain regions, ZI MCH neurons were the least excitable while LH MCH neurons were the most excitable. Furthermore, grouping MCH neurons according to CART co-expression revealed that MCH/CART− cells are uniquely depolarized and excitable, and display H-currents. These MCH/CART− cells were mainly found in the LH, which may in part explain why LH MCH neurons are more excitable. While some sex differences were found, the majority of parameters investigated were not different.DiscussionOur results suggest that MCH/CART− cells are electrophysiologically distinct, whereas MCH/CART+ cells are largely similar despite their diffuse distribution in the hypothalamus. It is therefore a combination of intrinsic electrophysiological properties and neurochemical identities, in addition to anatomy and connectivity that are likely to be critical in defining functional subpopulations of MCH neurons.
- Published
- 2025
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9. A Reinterpretation of the Relationship between Persistent and Resurgent Sodium Currents.
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Brown, Samuel P., Lawson, Ryan J., Moreno, Jonathan D., and Ransdell, Joseph L.
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SODIUM , *SODIUM channels , *DATA protection , *DYNAMIC testing , *ACTION potentials - Abstract
The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or noninactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the voltage-gated sodium conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow-inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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10. Variation and convergence in the morpho-functional properties of the mammalian neocortex.
- Author
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Mahon, Séverine
- Subjects
NEOCORTEX ,PYRAMIDAL neurons ,SIZE of brain ,FOREST density ,MARSUPIALS - Abstract
Man’s natural inclination to classify and hierarchize the living world has prompted neurophysiologists to explore possible differences in brain organisation between mammals, with the aim of understanding the diversity of their behavioural repertoires. But what really distinguishes the human brain from that of a platypus, an opossum or a rodent? In this review, we compare the structural and electrical properties of neocortical neurons in the main mammalian radiations and examine their impact on the functioning of the networks they form. We discuss variations in overall brain size, number of neurons, length of their dendritic trees and density of spines, acknowledging their increase in humans as in most large-brained species. Our comparative analysis also highlights a remarkable consistency, particularly pronounced in marsupial and placental mammals, in the cell typology, intrinsic and synaptic electrical properties of pyramidal neuron subtypes, and in their organisation into functional circuits. These shared cellular and network characteristics contribute to the emergence of strikingly similar large-scale physiological and pathological brain dynamics across a wide range of species. These findings support the existence of a core set of neural principles and processes conserved throughout mammalian evolution, from which a number of species-specific adaptations appear, likely allowing distinct functional needs to be met in a variety of environmental contexts. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
11. Glycine-induced activation of GPR158 increases the intrinsic excitability of medium spiny neurons in the nucleus accumbens.
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Aceto, Giuseppe, Nardella, Luca, Nanni, Simona, Pecci, Valeria, Bertozzi, Alessia, Nutarelli, Sofia, Viscomi, Maria Teresa, Colussi, Claudia, D'Ascenzo, Marcello, and Grassi, Claudio
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MEDIUM spiny neurons , *GLYCINE receptors , *NUCLEUS accumbens , *CENTRAL nervous system , *ACTION potentials , *G protein coupled receptors , *GLUTAMATE receptors , *BASAL ganglia - Abstract
It has been recently established that GPR158, a class C orphan G protein-coupled receptor, serves as a metabotropic glycine receptor. GPR158 is highly expressed in the nucleus accumbens (NAc), a major input structure of the basal ganglia that integrates information from cortical and subcortical structures to mediate goal-directed behaviors. However, whether glycine modulates neuronal activity in the NAc through GPR158 activation has not been investigated yet. Using whole-cell patch-clamp recordings, we found that glycine-dependent activation of GPR158 increased the firing rate of NAc medium spiny neurons (MSNs) while it failed to significantly affect the excitability of cholinergic interneurons (CIN). In MSNs GPR158 activation reduced the latency to fire, increased the action potential half-width, and reduced action potential afterhyperpolarization, effects that are all consistent with negative modulation of potassium M-currents, that in the central nervous system are mainly carried out by Kv7/KCNQ-channels. Indeed, we found that the GPR158-induced increase in MSN excitability was associated with decreased M-current amplitude, and selective pharmacological inhibition of the M-current mimicked and occluded the effects of GPR158 activation. In addition, when the protein kinase A (PKA) or extracellular signal-regulated kinase (ERK) signaling was pharmacologically blocked, modulation of MSN excitability by GPR158 activation was suppressed. Moreover, GPR158 activation increased the phosphorylation of ERK and Kv7.2 serine residues. Collectively, our findings suggest that GPR158/PKA/ERK signaling controls MSN excitability via Kv7.2 modulation. Glycine-dependent activation of GPR158 may significantly affect MSN firing in vivo, thus potentially mediating specific aspects of goal-induced behaviors. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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12. Plasticity mechanisms of genetically distinct Purkinje cells.
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Voerman, Stijn, Broersen, Robin, Swagemakers, Sigrid M. A., De Zeeuw, Chris I., and van der Spek, Peter J.
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PURKINJE cells , *PHYSIOLOGICAL adaptation , *ACTION potentials , *NEUROPLASTICITY , *PHYSIOLOGY , *CEREBELLAR cortex - Abstract
Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
13. Single cocaine exposure attenuates the intrinsic excitability of CRH neurons in the ventral BNST via Sigma-1 receptors
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Wu Jintao and Zhao Yue
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cocaine ,crh neurons ,ventral bnst ,intrinsic excitability ,sigma-1 receptors ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The ventral bed nucleus of the stria terminalis (vBNST) plays a key role in cocaine addiction, especially relapse. However, the direct effects of cocaine on corticotropin-releasing hormone (CRH) neurons in the vBNST remain unclear. Here, we identify that cocaine exposure can remarkably attenuate the intrinsic excitability of CRH neurons in the vBNST in vitro. Accumulating studies reveal the crucial role of Sigma-1 receptors (Sig-1Rs) in modulating cocaine addiction. However, to the authors’ best knowledge no investigations have explored the role of Sig-1Rs in the vBNST, let alone CRH neurons. Given that cocaine acts as a type of Sig-1Rs agonist, and the dramatic role of Sig-1Rs played in intrinsic excitability of neurons as well as cocaine addiction, we employ BD1063 a canonical Sig-1Rs antagonist to block the effects of cocaine, and significantly recover the excitability of CRH neurons. Together, we suggest that cocaine exposure leads to the firing rate depression of CRH neurons in the vBNST via binding to Sig-1Rs.
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- 2024
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14. Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to a successive stimulus
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Rienecker, Kira DA, Poston, Robert G, Segales, Joshua S, Finholm, Isabelle W, Sono, Morgan H, Munteanu, Sorina J, Ghaninejad-Esfahani, Mina, Rejepova, Ayna, Tejeda-Garibay, Susana, Wickman, Kevin, de Velasco, Ezequiel Marron Fernandez, Thayer, Stanley A, and Saha, Ramendra N
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Biomedical and Clinical Sciences ,Neurosciences ,Genetics ,Aetiology ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Underpinning research ,Neurological ,Action Potentials ,Animals ,Bicuculline ,Calcineurin ,Calcium ,GABA-A Receptor Antagonists ,Genes ,Immediate-Early ,Mitogen-Activated Protein Kinases ,Neurons ,Potassium ,Rats ,Receptors ,N-Methyl-D-Aspartate ,Transcription ,Genetic ,immediate early genes ,intrinsic excitability ,membrane depolarization ,neuronal activity ,transcription ,Chemical Sciences ,Biological Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
Immediate early genes (IEGs) are transcribed in response to neuronal activity from sensory stimulation during multiple adaptive processes in the brain. The transcriptional profile of IEGs is indicative of the duration of neuronal activity, but its sensitivity to the strength of depolarization remains unknown. Also unknown is whether activity history of graded potential changes influence future neuronal activity. In this work with dissociated rat cortical neurons, we found that mild depolarization-mediated by elevated extracellular potassium (K+)-induces a wide array of rapid IEGs and transiently depresses transcriptional and signaling responses to a successive stimulus. This latter effect was independent of de novo transcription, translation, and signaling via calcineurin or mitogen-activated protein kinase. Furthermore, as measured by multiple electrode arrays and calcium imaging, mild depolarization acutely subdues subsequent spontaneous and bicuculline-evoked activity via calcium- and N-methyl-d-aspartate receptor-dependent mechanisms. Collectively, this work suggests that a recent history of graded potential changes acutely depress neuronal intrinsic properties and subsequent responses. Such effects may have several potential downstream implications, including reducing signal-to-noise ratio during synaptic plasticity processes.
- Published
- 2022
15. Static Magnetic Field Stimulation Enhances Shunting Inhibition via a SLC26 Family Cl- Channel, Inducing Intrinsic Plasticity.
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Sinha, Adya Saran, Sumiya Shibata, Yasuyuki Takamatsu, Tenpei Akita, Atsuo Fukuda, and Tatsuya Mima
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MAGNETIC fields , *MEMBRANE potential , *ACTION potentials , *PYRAMIDAL neurons , *CARRIER proteins , *ELECTROSTATIC discharges - Abstract
Magnetic fields are being used for detailed anatomical and functional examination of the human brain. In addition, evidence for their efficacy in treatment of brain dysfunctions is accumulating. Transcranial static magnetic field stimulation (tSMS) is a recently developed technique for noninvasively modifying brain functions. In tSMS, a strong and small magnet when placed over the skull can temporarily suppress brain functions. Itsmodulatory effects persist beyond the time of stimulation. However, the neurophysiological mechanisms underlying tSMS-induced plasticity remain unclear. Here, using acute motor cortical slice preparation obtained from male C57BL/6N mice, we show that tSMS alters the intrinsic electrical properties of neurons by altering the activity of chloride (Cl-) channels in neurons. Exposure of mouse pyramidal neurons to a static magnetic field (SMF) at a strength similar to human tSMS temporarily decreased their excitability and induced transient neuronal swelling. The effects of SMF were blocked by DIDS and GlyH-101, but not by NPPB, consistent with the pharmacological profile of SLC26A11, a transporter protein with Cl- channel activity. Whole-cell voltage-clamp recordings of the GlyH-101-sensitive Cl- current component showed significant enhancement of the component at both subthreshold and depolarized membrane potentials after SMF application, resulting in shunting inhibition and reduced repetitive action potential (AP) firing at the respective potentials. Thus, this study provides the first neurophysiological evidence for the inhibitory effect of tSMS on neuronal activity and advances our mechanistic understanding of noninvasive human neuromodulation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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16. Variation and convergence in the morpho-functional properties of the mammalian neocortex
- Author
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Séverine Mahon
- Subjects
neocortex ,pyramidal neurons ,cortical circuits ,intrinsic excitability ,brain rhythms ,mammals ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Man's natural inclination to classify and hierarchize the living world has prompted neurophysiologists to explore possible differences in brain organisation between mammals, with the aim of understanding the diversity of their behavioural repertoires. But what really distinguishes the human brain from that of a platypus, an opossum or a rodent? In this review, we compare the structural and electrical properties of neocortical neurons in the main mammalian radiations and examine their impact on the functioning of the networks they form. We discuss variations in overall brain size, number of neurons, length of their dendritic trees and density of spines, acknowledging their increase in humans as in most large-brained species. Our comparative analysis also highlights a remarkable consistency, particularly pronounced in marsupial and placental mammals, in the cell typology, intrinsic and synaptic electrical properties of pyramidal neuron subtypes, and in their organisation into functional circuits. These shared cellular and network characteristics contribute to the emergence of strikingly similar large-scale physiological and pathological brain dynamics across a wide range of species. These findings support the existence of a core set of neural principles and processes conserved throughout mammalian evolution, from which a number of species-specific adaptations appear, likely allowing distinct functional needs to be met in a variety of environmental contexts.
- Published
- 2024
- Full Text
- View/download PDF
17. Increased Excitability of Layer 2 Cortical Pyramidal Neurons in the Supplementary Motor Cortex Underlies High Cocaine-Seeking Behaviors.
- Author
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Huang, Donald and Ma, Yao-Ying
- Subjects
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PYRAMIDAL neurons , *MOTOR neurons , *CINGULATE cortex , *SPRAGUE Dawley rats , *MOTOR cortex , *SUBSTANCE abuse relapse , *PREFRONTAL cortex - Abstract
Most efforts in addiction research have focused on the involvement of the medial prefrontal cortex, including the infralimbic, prelimbic, and anterior cingulate cortical areas, in cocaine-seeking behaviors. However, no effective prevention or treatment for drug relapse is available. We focused instead on the motor cortex, including both the primary and supplementary motor areas (M1 and M2, respectively). Addiction risk was evaluated by testing cocaine seeking after intravenous self-administration (IVSA) of cocaine in Sprague Dawley rats. The causal relationship between the excitability of cortical pyramidal neurons (CPNs) in M1/M2 and addiction risk was explored by ex vivo whole-cell patch clamp recordings and in vivo pharmacological or chemogenetic manipulation. Our recordings showed that on withdrawal day 45 (WD45) after IVSA, cocaine, but not saline, increased the excitability of CPNs in the cortical superficial layers (primarily layer 2, denoted L2) but not in layer 5 (L5) in M2. Bilateral microinjection of the GABA A (gamma-aminobutyric acid A) receptor agonist muscimol to the M2 area attenuated cocaine seeking on WD45. More specifically, chemogenetic inhibition of CPN excitability in L2 of M2 (denoted M2-L2) by the DREADD (designer receptor exclusively activated by designer drugs) agonist compound 21 prevented drug seeking on WD45 after cocaine IVSA. This chemogenetic inhibition of M2-L2 CPNs had no effects on sucrose seeking. In addition, neither pharmacological nor chemogenetic inhibition manipulations altered general locomotor activity. Our results indicate that cocaine IVSA induces hyperexcitability in the motor cortex on WD45. Importantly, the increased excitability in M2, particularly in L2, could be a novel target for preventing drug relapse during withdrawal. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
18. Cocaine Exposure Increases Excitatory Synaptic Transmission and Intrinsic Excitability in the Basolateral Amygdala in Male and Female Rats and across the Estrous Cycle.
- Author
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Corbett, Claire M., Miller, Emily N.D., Wannen, Erin E., Rood, Benjamin D, Chandler, Daniel J., and Loweth, Jessica A.
- Subjects
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ESTRUS , *NEURAL transmission , *PATCH-clamp techniques (Electrophysiology) , *AMYGDALOID body , *PYRAMIDAL neurons - Abstract
Introduction: Sex and ovarian hormones influence cocaine seeking and relapse vulnerability, but less is known regarding the cellular and synaptic mechanisms contributing to these behavioral sex differences. One factor thought to influence cue-induced seeking behavior following withdrawal is cocaine-induced changes in the spontaneous activity of pyramidal neurons in the basolateral amygdala (BLA). However, the mechanisms underlying these changes, including potential sex or estrous cycle effects, are unknown. Methods: Ex vivo whole-cell patch clamp electrophysiology was conducted to investigate the effects of cocaine exposure, sex, and estrous cycle fluctuations on two properties that can influence spontaneous activity of BLA pyramidal neurons: (1) frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) and (2) intrinsic excitability. Recordings of BLA pyramidal neurons were conducted in adult male and female rats and across the estrous cycle following 2–4 weeks of withdrawal from extended-access cocaine self-administration (6 h/day for 10 days) or drug-naïve conditions. Results: In both sexes, cocaine exposure increased the frequency, but not amplitude, of sEPSCs and neuronal intrinsic excitability. Across the estrous cycle, sEPSC frequency and intrinsic excitability were significantly elevated only in cocaine-exposed females in the estrus stage of the cycle, a stage when cocaine-seeking behavior is known to be enhanced. Conclusions: Here, we identify potential mechanisms underlying cocaine-induced alterations in the spontaneous activity of BLA pyramidal neurons in both sexes along with changes in these properties across the estrous cycle. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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19. Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony
- Author
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Chang, Che-Wei, Evans, Mark D, Yu, Xinxing, Yu, Gui-Qiu, and Mucke, Lennart
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Biological Sciences ,Alzheimer's Disease ,Dementia ,Acquired Cognitive Impairment ,Aging ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurosciences ,Neurodegenerative ,Aetiology ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Neurological ,Alzheimer Disease ,Animals ,Cells ,Cultured ,Epilepsy ,Excitatory Postsynaptic Potentials ,Female ,Inhibitory Postsynaptic Potentials ,Interneurons ,Male ,Mice ,129 Strain ,Mice ,Inbred C57BL ,Mice ,Knockout ,Neural Inhibition ,Neural Pathways ,Neuronal Plasticity ,Pyramidal Cells ,Somatosensory Cortex ,Time Factors ,tau Proteins ,Alzheimer’s disease ,axon initial segment ,epilepsy ,excitation-inhibition balance ,hypersynchrony ,interneurons ,intrinsic excitability ,neuronal plasticity ,pyramidal cells ,tau ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - Abstract
The protein tau has been implicated in many brain disorders. In animal models, tau reduction suppresses epileptogenesis of diverse causes and ameliorates synaptic and behavioral abnormalities in various conditions associated with excessive excitation-inhibition (E/I) ratios. However, the underlying mechanisms are unknown. Global genetic ablation of tau in mice reduces the action potential (AP) firing and E/I ratio of pyramidal cells in acute cortical slices without affecting the excitability of these cells. Tau ablation reduces the excitatory inputs to inhibitory neurons, increases the excitability of these cells, and structurally alters their axon initial segments (AISs). In primary neuronal cultures subjected to prolonged overstimulation, tau ablation diminishes the homeostatic response of AISs in inhibitory neurons, promotes inhibition, and suppresses hypersynchrony. Together, these differential alterations in excitatory and inhibitory neurons help explain how tau reduction prevents network hypersynchrony and counteracts brain disorders causing abnormally increased E/I ratios.
- Published
- 2021
20. Investigating the effect of amyloid-beta on hippocampal dynamics in Alzheimer's disease
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Warburton, Julia M. and Marucci, Lucia
- Subjects
616.8 ,Alzheimer's disease ,Amyloid-beta ,Hippocampus ,Computational ,CA1 ,Biophysical ,Gamma oscillations ,Intrinsic excitability ,mEPSC - Abstract
Alzheimer's disease (AD) is a complex and multifactorial, neurodegenerative disease. Accumulation of pathogenic forms of the protein amyloid-beta (Aβ), one of the hallmark features of AD, is thought to have a causal role in this neurodegeneration. Enhanced levels of Aβ are associated with synaptic dysfunction, altered neuronal intrinsic excitability and altered gamma frequency activity within the hippocampus. In this thesis, biophysical models of synapses, neurons and networks are combined with experimental work to examine how Aβ alters neural activity in the CA1 hippocampal region. The acute effect of Aβ-infusion on synaptic transmission is investigated by recording spontaneous miniature excitatory postsynaptic currents (mEPSCs) from CA1 neurons in cultured hippocampal slices; Aβ is found to cause a rapid increase in mEPSC amplitude. Using a first-order kinetic synapse model parameterised using the mEPSC data it is found that the increase in amplitude can be accounted for by a 50% increase in the synaptic conductance of the model. Two versions of a single-compartment biophysical model are used to simulate intrinsic excitability measures recorded from CA1 pyramidal neurons in wild type and PDAPP transgenic mice that overexpress Aβ. Both models predict that altered excitability in PDAPP neurons can be accounted for by lowering the transient Na⁺ and delayed-rectifier K⁺ (K_DR) channel conductances and by slowing the activation rate of the K_DR-channel. The potential impacts of these observations on gamma frequency oscillations are explored using an excitatory-inhibitory network model. The Aβ-mediated increase in synaptic transmission increases the total gamma power of the oscillations, progressively increasing as more synapses are affected. Incorporating the PDAPP neuron model into the network increases the frequency of the gamma oscillations. These results illustrate how data-informed mathematical models can bring new insights into the underlying mechanisms and implications of Aβ pathology and can contribute to a quantitative and multiscale understanding of AD.
- Published
- 2021
21. Synaptic and intrinsic plasticity within overlapping lateral amygdala ensembles following fear conditioning.
- Author
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Sehgal, Megha, Ehlers, Vanessa E., and Moyer Jr., James R.
- Subjects
NEUROPLASTICITY ,AMYGDALOID body ,NEURONS - Abstract
Introduction: New learning results in modulation of intrinsic plasticity in the underlying brain regions. Such changes in intrinsic plasticity can influence allocation and encoding of future memories such that new memories encoded during the period of enhanced excitability are linked to the original memory. The temporal window during which the two memories interact depends upon the time course of intrinsic plasticity following new learning. Methods: Using the well-characterized lateral amygdala-dependent auditory fear conditioning as a behavioral paradigm, we investigated the time course of changes in intrinsic excitability within lateral amygdala neurons. Results: We found transient changes in the intrinsic excitability of amygdala neurons. Neuronal excitability was increased immediately following fear conditioning and persisted for up to 4 days post-learning but was back to naïve levels 10 days following fear conditioning. We also determined the relationship between learning-induced intrinsic and synaptic plasticity. Synaptic plasticity following fear conditioning was evident for up to 24 h but not 4 days later. Importantly, we demonstrated that the enhanced neuronal intrinsic excitability was evident in many of the same neurons that had undergone synaptic plasticity immediately following fear conditioning. Interestingly, such a correlation between synaptic and intrinsic plasticity following fear conditioning was no longer present 24 h post-learning. Discussion: These data demonstrate that intrinsic and synaptic changes following fear conditioning are transient and co-localized to the same neurons. Since intrinsic plasticity following fear conditioning is an important determinant for the allocation and consolidation of future amygdala-dependent memories, these findings establish a time course during which fear memories may influence each other. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
22. NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long‐term potentiation of CA3 pyramidal cells.
- Author
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Márquez, Luis A., Griego, Ernesto, López Rubalcava, Carolina, and Galván, Emilio J.
- Subjects
- *
PYRAMIDAL neurons , *LONG-term potentiation , *METHYL aspartate receptors , *NEUROPLASTICITY , *DENTATE gyrus - Abstract
Experimental manipulations that interfere with the functional expression of N‐methyl‐D‐aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK‐801 during early postnatal development alters glutamate release and impairs the induction of NMDAR‐dependent long‐term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR)‐mediated short‐ and long‐term potentiation, are compromised in response to neonatal treatment with MK‐801. Consistent with this tenet, short‐ and long‐term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole‐cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre‐ and postsynaptic modifications at the MF—CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired‐pulse ratio, and reduced AMPAR‐mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK‐801‐treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR‐independent forms of synaptic plasticity of the hippocampus. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
23. Synaptic and intrinsic plasticity within overlapping lateral amygdala ensembles following fear conditioning
- Author
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Megha Sehgal, Vanessa E. Ehlers, and James R. Moyer
- Subjects
intrinsic excitability ,fear learning ,lateral amygdala ,synaptic plasticity ,spike frequency adaptation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionNew learning results in modulation of intrinsic plasticity in the underlying brain regions. Such changes in intrinsic plasticity can influence allocation and encoding of future memories such that new memories encoded during the period of enhanced excitability are linked to the original memory. The temporal window during which the two memories interact depends upon the time course of intrinsic plasticity following new learning.MethodsUsing the well-characterized lateral amygdala-dependent auditory fear conditioning as a behavioral paradigm, we investigated the time course of changes in intrinsic excitability within lateral amygdala neurons.ResultsWe found transient changes in the intrinsic excitability of amygdala neurons. Neuronal excitability was increased immediately following fear conditioning and persisted for up to 4 days post-learning but was back to naïve levels 10 days following fear conditioning. We also determined the relationship between learning-induced intrinsic and synaptic plasticity. Synaptic plasticity following fear conditioning was evident for up to 24 h but not 4 days later. Importantly, we demonstrated that the enhanced neuronal intrinsic excitability was evident in many of the same neurons that had undergone synaptic plasticity immediately following fear conditioning. Interestingly, such a correlation between synaptic and intrinsic plasticity following fear conditioning was no longer present 24 h post-learning.DiscussionThese data demonstrate that intrinsic and synaptic changes following fear conditioning are transient and co-localized to the same neurons. Since intrinsic plasticity following fear conditioning is an important determinant for the allocation and consolidation of future amygdala-dependent memories, these findings establish a time course during which fear memories may influence each other.
- Published
- 2023
- Full Text
- View/download PDF
24. Temporal dynamics of Na/K pump mediated memory traces: insights from conductance-based models of Drosophila neurons.
- Author
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Megwa, Obinna F., Pascual, Leila May, Günay, Cengiz, Pulver, Stefan R., and Prinz, Astrid A.
- Subjects
DROSOPHILA ,MOTOR neurons ,NEURONS ,ANIMAL behavior ,NEURAL circuitry ,LONG-term potentiation - Abstract
Sodium potassium ATPases (Na/K pumps) mediate long-lasting, dynamic cellular memories that can last tens of seconds. The mechanisms controlling the dynamics of this type of cellular memory are not well understood and can be counterintuitive. Here, we use computational modeling to examine how Na/K pumps and the ion concentration dynamics they influence shape cellular excitability. In a Drosophila larval motor neuron model, we incorporate a Na/K pump, a dynamic intracellular Na+ concentration, and a dynamic Na+ reversal potential. We probe neuronal excitability with a variety of stimuli, including step currents, ramp currents, and zap currents, then monitor the sub- and suprathreshold voltage responses on a range of time scales. We find that the interactions of a Na+-dependent pump current with a dynamic Na+ concentration and reversal potential endow the neuron with rich response properties that are absent when the role of the pump is reduced to the maintenance of constant ion concentration gradients. In particular, these dynamic pump-Na+ interactions contribute to spike rate adaptation and result in long-lasting excitability changes after spiking and even after sub-threshold voltage fluctuations on multiple time scales. We further show that modulation of pump properties can profoundly alter a neuron's spontaneous activity and response to stimuli by providing a mechanism for bursting oscillations. Our work has implications for experimental studies and computational modeling of the role of Na/K pumps in neuronal activity, information processing in neural circuits, and the neural control of animal behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
25. Missense mutations in the membrane domain of PRRT2 affect its interaction with Nav1.2 voltage-gated sodium channels
- Author
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Bruno Sterlini, Francesca Franchi, Lisastella Morinelli, Beatrice Corradi, Chiara Parodi, Martina Albini, Alessandra Bianchi, Antonella Marte, Pietro Baldelli, Giulio Alberini, Luca Maragliano, Pierluigi Valente, Fabio Benfenati, and Anna Corradi
- Subjects
Proline-rich transmembrane protein-2 ,Voltage-dependent sodium channels ,Molecular dynamics ,Intrinsic excitability ,Paroxysmal kinesigenic dyskinesia ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
PRRT2 is a neuronal protein that controls neuronal excitability and network stability by modulating voltage-gated Na+ channel (Nav). PRRT2 pathogenic variants cause pleiotropic syndromes including epilepsy, paroxysmal kinesigenic dyskinesia and episodic ataxia attributable to loss-of-function pathogenetic mechanism. Based on the evidence that the transmembrane domain of PRRT2 interacts with Nav1.2/1.6, we focused on eight missense mutations located within the domain that show expression and membrane localization similar to the wild-type protein. Molecular dynamics simulations showed that the mutants do not alter the structural stability of the PRRT2 membrane domain and preserve its conformation. Using affinity assays, we found that the A320V and V286M mutants displayed respectively decreased and increased binding to Nav1.2. Accordingly, surface biotinylation showed an increased Nav1.2 surface exposure induced by the A320V mutant. Electrophysiological analysis confirmed the lack of modulation of Nav1.2 biophysical properties by the A320V mutant with a loss-of-function phenotype, while the V286M mutant displayed a gain-of-function with respect to wild-type PRRT2 with a more pronounced left-shift of the inactivation kinetics and delayed recovery from inactivation. The data confirm the key role played by the PRRT2-Nav interaction in the pathogenesis of the PRRT2-linked disorders and suggest an involvement of the A320 and V286 residues in the interaction site. Given the similar clinical phenotype caused by the two mutations, we speculate that circuit instability and paroxysmal manifestations may arise when PRRT2 function is outside the physiological range.
- Published
- 2023
- Full Text
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26. Temporal dynamics of Na/K pump mediated memory traces: insights from conductance-based models of Drosophila neurons
- Author
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Obinna F. Megwa, Leila May Pascual, Cengiz Günay, Stefan R. Pulver, and Astrid A. Prinz
- Subjects
Drosophila larvae ,motor neuron ,sodium potassium pump ,intrinsic excitability ,sodium equilibrium potential ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Sodium potassium ATPases (Na/K pumps) mediate long-lasting, dynamic cellular memories that can last tens of seconds. The mechanisms controlling the dynamics of this type of cellular memory are not well understood and can be counterintuitive. Here, we use computational modeling to examine how Na/K pumps and the ion concentration dynamics they influence shape cellular excitability. In a Drosophila larval motor neuron model, we incorporate a Na/K pump, a dynamic intracellular Na+ concentration, and a dynamic Na+ reversal potential. We probe neuronal excitability with a variety of stimuli, including step currents, ramp currents, and zap currents, then monitor the sub- and suprathreshold voltage responses on a range of time scales. We find that the interactions of a Na+-dependent pump current with a dynamic Na+ concentration and reversal potential endow the neuron with rich response properties that are absent when the role of the pump is reduced to the maintenance of constant ion concentration gradients. In particular, these dynamic pump-Na+ interactions contribute to spike rate adaptation and result in long-lasting excitability changes after spiking and even after sub-threshold voltage fluctuations on multiple time scales. We further show that modulation of pump properties can profoundly alter a neuron’s spontaneous activity and response to stimuli by providing a mechanism for bursting oscillations. Our work has implications for experimental studies and computational modeling of the role of Na/K pumps in neuronal activity, information processing in neural circuits, and the neural control of animal behavior.
- Published
- 2023
- Full Text
- View/download PDF
27. Gamma frequency entrainment rescues cognitive impairment by decreasing postsynaptic transmission after traumatic brain injury.
- Author
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Weijie Wang, Xiaotian Zhang, Ruixing He, Shaoxun Li, Dazhao Fang, and Cong Pang
- Subjects
- *
BRAIN injuries , *COGNITION disorders , *PYRAMIDAL neurons , *LONG-term potentiation - Abstract
Introduction: The relationship between oscillatory activity in hippocampus and cognitive impairment in traumatic brain injury (TBI) remains unclear. Although TBI decreases gamma oscillations and 40 Hz light flicker improves TBI prognosis, the effects and mechanism of rhythmic flicker on TBI remain unclear. Aims: In this study, we aimed to explore whether light flicker could reverse cognitive deficits, and further explore its potential mechanisms in TBI mouse model. Methods: The Morris water maze test (MWM), step-down test (SDT), and novel object recognition test (NOR) were applied to evaluate the cognitive ability. The local field potential (LFP) recording was applied to measure low gamma reduction of CA1 in hippocampus after TBI. And electrophysiological experiments were applied to explore effects of the gamma frequency entrainment on long-term potentiation (LTP), postsynaptic transmission, and intrinsic excitability of CA1 pyramidal cells (PCs) in TBI mice. Immunofluorescence staining and western blotting were applied to explore the effects of 40 Hz light flicker on the expression of PSD95 in hippocampus of TBI mice. Results: We found that 40 Hz light flicker restored low gamma reduction of CA1 in hippocampus after TBI. And 40 Hz, but not random or 80 Hz light flicker, reversed cognitive impairment after TBI in behavioral tests. Moreover, 40 Hz light flicker improved N-methyl-D-aspartate (NMDA) receptor-dependent LTP (LTPNMDAR) and Ltype voltage-gated calcium channel-dependent LTP (LTPL-VGCC) after TBI treatment. And gamma frequency entrainment decreased excitatory postsynaptic currents (EPSCs) of CA1 PCs in TBI mice. Our results have illustrated that 40 Hz light flicker could decrease intrinsic excitability of PCs after TBI treatment in mice. Furthermore, 40 Hz light flicker decreased the expression of PSD95 in hippocampus of TBI mice. Conclusion: These results demonstrated that 40 Hz light flicker rescues cognitive impairment by decreasing postsynaptic transmission in PCs after TBI treatment in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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28. Endogenous Modulators of NMDA Receptor Control Dendritic Field Expansion of Cortical Neurons.
- Author
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Jorratt, Pascal, Ricny, Jan, Leibold, Christian, and Ovsepian, Saak V.
- Abstract
Impairments of N-methyl-D-aspartate receptor (NMDAR) activity have been implicated in several neuropsychiatric disorders, with pharmacological inhibition of NMDAR-mediated currents and associated neurobehavioral changes considered as a model of schizophrenia. We analyzed the effects of brief and long-term exposure of rat cortical cultures to the most prevalent endogenous modulators of NMDAR (kynurenic acid, pregnenolone sulfate, spermidine, and zinc) on neuronal viability, stimulation-induced release of glutamate, and dendritic morphology with synaptic density. Both, glutamate release and neuronal viability studies revealed no difference between the test and control groups. No differences were also observed in the number of dendritic branching and length, or density of synaptic connections and neuronal soma size. Comparison of the extent of dendritic projections and branching patterns, however, revealed enhanced distal arborization with the expansion of the dendritic area under prolonged treatment of cultures with physiological concentrations of NMDAR modulators, with differences reaching significance in spermidine and pregnenolone sulfate tests. Measurements of the density of glutamatergic synapses showed consistency across all neuronal groups, except those treated with pregnenolone sulfate, which showed a reduction of PSD-95–positive elements. Overall, our data suggest that constitutive glutamatergic activity mediated by NMDAR controls the dendritic field expansion and can influence the integrative properties of cortical neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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29. A Push–Pull Mechanism Between PRRT2 and β4-subunit Differentially Regulates Membrane Exposure and Biophysical Properties of NaV1.2 Sodium Channels.
- Author
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Valente, Pierluigi, Marte, Antonella, Franchi, Francesca, Sterlini, Bruno, Casagrande, Silvia, Corradi, Anna, Baldelli, Pietro, and Benfenati, Fabio
- Abstract
Proline-rich transmembrane protein 2 (PRRT2) is a neuron-specific protein implicated in the control of neurotransmitter release and neural network stability. Accordingly, PRRT2 loss-of-function mutations associate with pleiotropic paroxysmal neurological disorders, including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. PRRT2 is a negative modulator of the membrane exposure and biophysical properties of Na
+ channels NaV 1.2/NaV 1.6 predominantly expressed in brain glutamatergic neurons. NaV channels form complexes with β-subunits that facilitate the membrane targeting and the activation of the α-subunits. The opposite effects of PRRT2 and β-subunits on NaV channels raises the question of whether PRRT2 and β-subunits interact or compete for common binding sites on the α-subunit, generating Na+ channel complexes with distinct functional properties. Using a heterologous expression system, we have observed that β-subunits and PRRT2 do not interact with each other and act as independent non-competitive modulators of NaV 1.2 channel trafficking and biophysical properties. PRRT2 antagonizes the β4-induced increase in expression and functional activation of the transient and persistent NaV 1.2 currents, without affecting resurgent current. The data indicate that β4-subunit and PRRT2 form a push–pull system that finely tunes the membrane expression and function of NaV channels and the intrinsic neuronal excitability. [ABSTRACT FROM AUTHOR]- Published
- 2023
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30. Enhanced GABAergic Tonic Inhibition Reduces Intrinsic Excitability of Hippocampal CA1 Pyramidal Cells in Experimental Autoimmune Encephalomyelitis
- Author
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Kammel, Laura G, Wei, Weizheng, Jami, Shekib A, Voskuhl, Rhonda R, and O'Dell, Thomas J
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurosciences ,Multiple Sclerosis ,Neurodegenerative ,Autoimmune Disease ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Animals ,CA1 Region ,Hippocampal ,Encephalomyelitis ,Autoimmune ,Experimental ,GABA-A Receptor Antagonists ,Long-Term Potentiation ,Mice ,Neural Inhibition ,Patch-Clamp Techniques ,Pyramidal Cells ,Pyridazines ,Synaptic Transmission ,multiple sclerosis ,experimental autoimmune encephalomyelitis ,hippocampus ,inhibitory synaptic transmission ,tonic inhibition ,intrinsic excitability ,long-term potentiation ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Cognitive impairment (CI), a debilitating and pervasive feature of multiple sclerosis (MS), is correlated with hippocampal atrophy. Findings from postmortem MS hippocampi indicate that expression of genes involved in both excitatory and inhibitory neurotransmission are altered in MS, and although deficits in excitatory neurotransmission have been reported in the MS model experimental autoimmune encephalomyelitis (EAE), the functional consequence of altered inhibitory neurotransmission remains poorly understood. In this study, we used electrophysiological and biochemical techniques to examine inhibitory neurotransmission in the CA1 region of the hippocampus in EAE. We find that tonic, GABAergic inhibition is enhanced in CA1 pyramidal cells from EAE mice. Although plasma membrane expression of the GABA transporter GAT-3 was decreased in the EAE hippocampus, an increased surface expression of α5 subunit-containing GABAA receptors appears to be primarily responsible for the increase in tonic inhibition during EAE. Enhanced tonic inhibition during EAE was associated with decreased CA1 pyramidal cell excitability and inhibition of α5 subunit-containing GABAA receptors with the negative allosteric modulator L-655,708 enhanced pyramidal cell excitability in EAE mice. Together, our results suggest that altered GABAergic neurotransmission may underlie deficits in hippocampus-dependent cognitive function in EAE and MS.
- Published
- 2018
31. Rapid Disinhibition by Adjustment of PV Intrinsic Excitability during Whisker Map Plasticity in Mouse S1
- Author
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Gainey, Melanie A, Aman, Joseph W, and Feldman, Daniel E
- Subjects
Neurosciences ,Animals ,Brain Mapping ,Electrophysiological Phenomena ,Evoked Potentials ,Motor ,Female ,Homeostasis ,Mice ,Mice ,Inbred C57BL ,Neural Conduction ,Neuronal Plasticity ,Neurons ,Optogenetics ,Parvalbumins ,Potassium Channels ,Voltage-Gated ,Pyramidal Cells ,Somatosensory Cortex ,Vibrissae ,feedforward inhibition ,homeostasis ,intrinsic excitability ,plasticity ,PV neuron ,sensory cortex ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Rapid plasticity of layer (L) 2/3 inhibitory circuits is an early step in sensory cortical map plasticity, but its cellular basis is unclear. We show that, in mice of either sex, 1 d whisker deprivation drives the rapid loss of L4-evoked feedforward inhibition and more modest loss of feedforward excitation in L2/3 pyramidal (PYR) cells, increasing the excitation-inhibition conductance ratio. Rapid disinhibition was due to reduced L4-evoked spiking by L2/3 parvalbumin (PV) interneurons, caused by reduced PV intrinsic excitability. This included elevated PV spike threshold, which is associated with an increase in low-threshold, voltage-activated delayed rectifier (presumed Kv1) and A-type potassium currents. Excitatory synaptic input and unitary inhibitory output of PV cells were unaffected. Functionally, the loss of feedforward inhibition and excitation was precisely coordinated in L2/3 PYR cells, so that peak feedforward synaptic depolarization remained stable. Thus, the rapid plasticity of PV intrinsic excitability offsets early weakening of excitatory circuits to homeostatically stabilize synaptic potentials in PYR cells of sensory cortex.SIGNIFICANCE STATEMENT Inhibitory circuits in cerebral cortex are highly plastic, but the cellular mechanisms and functional importance of this plasticity are incompletely understood. We show that brief (1 d) sensory deprivation rapidly weakens parvalbumin (PV) inhibitory circuits by reducing the intrinsic excitability of PV neurons. This involved a rapid increase in voltage-gated potassium conductances that control near-threshold spiking excitability. Functionally, the loss of PV-mediated feedforward inhibition in L2/3 pyramidal cells was precisely balanced with the separate loss of feedforward excitation, resulting in a net homeostatic stabilization of synaptic potentials. Thus, rapid plasticity of PV intrinsic excitability implements network-level homeostasis to stabilize synaptic potentials in sensory cortex.
- Published
- 2018
32. Brain-derived neurotrophic factor is a regulator of synaptic transmission in the adult visual thalamus.
- Author
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Van Hook, Matthew J.
- Subjects
- *
BRAIN-derived neurotrophic factor , *SYNAPSES , *NEUROPLASTICITY , *NEURAL transmission , *THALAMIC nuclei , *RETINAL ganglion cells , *THALAMOCORTICAL system , *SYNAPTIC vesicles , *THALAMUS - Abstract
Brain-derived neurotrophic factor (BDNF) is an important regulator of circuit development, neuronal survival, and plasticity throughout the nervous system. In the visual system, BDNF is produced by retinal ganglion cells (RGCs) and transported along their axons to central targets. Within the dorsolateral geniculate nucleus (dLGN), a key RGC projection target for conscious vision, the BDNF receptor tropomyosin receptor kinase B (TrkB) is present on RGC axon terminals and postsynaptic thalamocortical (TC) relay neuron dendrites. Based on this, the goal of this study was to determine how BDNF modulates the conveyance of signals through the retinogeniculate (RG) pathway of adult mice. Application of BDNF to dLGN brain slices increased TC neuron spiking evoked by optogenetic stimulation of RGC axons. There was a modest contribution to this effect from a BDNF-dependent enhancement of TC neuron intrinsic excitability including increased input resistance and membrane depolarization. BDNF also increased evoked vesicle release from RGC axon terminals, as evidenced by increased amplitude of evoked excitatory postsynaptic currents (EPSCs), which was blocked by inhibition of TrkB or phospholipase C. High-frequency stimulation revealed that BDNF increased synaptic vesicle pool size, release probability, and replenishment rate. There was no effect of BDNF on EPSC amplitude or short-term plasticity of corticothalamic feedback synapses. Thus, BDNF regulates RG synapses by both presynaptic and postsynaptic mechanisms. These findings suggest that BNDF influences the flow of visual information through the retinogeniculate pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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33. β-adrenergic receptor-induced E-S potentiation in the dorsal and ventral hippocampus.
- Author
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Trompoukis G, Miliou A, and Papatheodoropoulos C
- Abstract
β-adrenergic receptors (β-ARs) play a critical role in modulating learning, memory, emotionality, and long-term synaptic plasticity. Recent studies indicate that β-ARs are necessary for long-term potentiation (LTP) induction in the ventral hippocampus under moderate synaptic activation conditions that do not typically induce LTP. To explore potential dorsoventral differences in β-AR-mediated effects, we applied the β-AR agonist isoproterenol (10 μM, 30 min) to dorsal and ventral hippocampal slices, recording field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) from the CA1 region. Isoproterenol induced robust, long-lasting PS increases, with effects three times greater in the dorsal compared to the ventral hippocampus. Isoproterenol did not significantly affect fEPSP in either segment of the hippocampus, leading to strong excitatory-to-spike (E-S) potentiation-twice as large as that in the ventral hippocampus. E-S potentiation was not associated with significant paired-pulse inhibition changes in either hippocampal segment. These differences do not appear to result from β1-AR expression levels, as they are comparable across dorsal and ventral hippocampal regions. Overall, the findings suggest that β-AR activation enhances the dorsal hippocampus's role during stress, facilitating heightened alertness, rapid spatial information processing, and effective navigation necessary for "fight-or-flight" responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Trompoukis, Miliou and Papatheodoropoulos.)
- Published
- 2024
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34. Cranial irradiation impairs intrinsic excitability and synaptic plasticity of hippocampal CA1 pyramidal neurons with implications for cognitive function
- Author
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Min-Yi Wu, Wen-Jun Zou, Pei Yu, Yuhua Yang, Shao-Jian Li, Qiang Liu, Jiatian Xie, Si-Qi Chen, Wei-Jye Lin, and Yamei Tang
- Subjects
gaba-mediated hyperfunction ,glur ,intrinsic excitability ,long-term potentiation ,radiation-induced cognitive impairment ,spontaneous excitatory postsynaptic currents ,spontaneous inhibitory postsynaptic currents ,synaptic plasticity ,type i vesicular glutamate transporter ,vesicular gaba transporter ,whole-cell patch clamp recording ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Radiation therapy is a standard treatment for head and neck tumors. However, patients often exhibit cognitive impairments following radiation therapy. Previous studies have revealed that hippocampal dysfunction, specifically abnormal hippocampal neurogenesis or neuroinflammation, plays a key role in radiation-induced cognitive impairment. However, the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized. We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min. Furthermore, we observed a remarkable reduction in spike firing and excitatory synaptic input, as well as greatly enhanced inhibitory inputs, in hippocampal CA1 pyramidal neurons. Corresponding to the electrophysiological adaptation, we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT. Furthermore, in irradiated mice, long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited. These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.
- Published
- 2022
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35. Acute restraint stress impairs histamine type 2 receptor ability to increase the excitability of medium spiny neurons in the nucleus accumbens
- Author
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Giuseppe Aceto, Luca Nardella, Giacomo Lazzarino, Barbara Tavazzi, Alessia Bertozzi, Simona Nanni, Claudia Colussi, Marcello D'Ascenzo, and Claudio Grassi
- Subjects
Acute restraint stress ,Histamine ,H2 receptor ,Kv4.2 ,Nucleus accumbens ,Intrinsic excitability ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Histamine, a monoamine implicated in stress-related arousal states, is synthesized in neurons exclusively located in the hypothalamic tuberomammillary nucleus (TMN) from where they diffusely innervate striatal and mesolimbic networks including the nucleus accumbens (NAc), a vital node in the limbic loop. Since histamine-containing TMN neuron output increases during stress, we hypothesized that exposure of mice to acute restrain stress (ARS) recruits endogenous histamine type 2 receptor (H2R) signaling in the NAc, whose activation increases medium spiny neurons (MSNs) intrinsic excitability via downregulation of A-type K+ currents. We employed an ARS paradigm in which mice were restrained for 120 min, followed by a 20-min recovery period, after which brain slices were prepared for ex vivo electrophysiology. Using whole-cell patch-clamp recordings, we found that pharmacological activation of H2R failed to affect MSN excitability and A-type K+ currents in mice that underwent ARS. Interestingly, in mice treated with H2R-antagonist prior to ARS paradigm, H2R activation increased evoked firing and decreased A-type K+ currents similarly to what observed in control mice. Furthermore, H2R-antagonist treatment ameliorated anxiety-like behavior in ARS mice. Together, our findings indicate that ARS paradigm recruits endogenous H2R signaling in MSNs and suggest the involvement of H2R signaling in stress-related motivational states.
- Published
- 2022
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36. Maternal immune activation increases excitability via downregulation of A-type potassium channels and reduces dendritic complexity of hippocampal neurons of the offspring.
- Author
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Griego, Ernesto, Segura-Villalobos, Deisy, Lamas, Mónica, and Galván, Emilio J.
- Subjects
- *
MATERNAL immune activation , *POTASSIUM channels , *PYRAMIDAL neurons , *NEURONS , *ACTION potentials - Abstract
• LPS injection during pregnancy (MIA) increases cytokines production and decreases litter size. • MIA increases intrinsic excitability, alters action potentials kinetics of hippocampal neurons. • MIA alters functionality and biophysical properties of multiple ion channels. • MIA impairs anatomical development and reduces the dendritic complexity. • MIA alters the excitation–inhibition balance of hippocampal neurons. The epidemiological association between bacterial or viral maternal infections during pregnancy and increased risk for developing psychiatric disorders in offspring is well documented. Numerous rodent and non-human primate studies of viral- or, to a lesser extent, bacterial-induced maternal immune activation (MIA) have documented a series of neurological alterations that may contribute to understanding the pathophysiology of schizophrenia and autism spectrum disorders. Long-term neuronal and behavioral alterations are now ascribed to the effect of maternal proinflammatory cytokines rather than the infection itself. However, detailed electrophysiological alterations in brain areas relevant to psychiatric disorders, such as the dorsal hippocampus, are lacking in response to bacterial-induced MIA. This study determined if electrophysiological and morphological alterations converge in CA1 pyramidal cells (CA1 PC) from the dorsal hippocampus in bacterial-induced MIA offspring. A series of changes in the functional expression of K+ and Na+ ion channels altered the passive and active membrane properties and triggered hyperexcitability of CA1 PC. Contributing to the hyperexcitability, the somatic A-type potassium current (I A) was decreased in MIA CA1 PC. Likewise, the spontaneous glutamatergic and GABAergic inputs were dysregulated and biased toward increased excitation, thereby reshaping the excitation–inhibition balance. Consistent with these findings, the dendritic branching complexity of MIA CA1 PC was reduced. Together, these morphophysiological alterations modify CA1 PC computational capabilities and contribute to explaining cellular alterations that may underlie the cognitive symptoms of MIA-associated psychiatric disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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37. The ethanol inhibition of basolateral amygdala neuron spiking is mediated by a γ‐aminobutyric acid type A‐mediated tonic current.
- Author
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Nimitvilai‐Roberts, Sudarat and Woodward, John J.
- Subjects
- *
NEURONS , *ANIMAL experimentation , *ELECTROPHYSIOLOGY , *GABA , *ACTION potentials , *ETHANOL , *AMYGDALOID body , *NEUROGLIA , *MICE , *MEMBRANE potential - Abstract
Background: The basolateral nucleus of the amygdala (BLA) plays an important role in the development of fear and anxiety‐related behaviors. The BLA receives inputs from all sensory stimuli. After processing those stimuli, BLA neurons signal neurons within the central amygdala and other brain regions, including the ventral and dorsal striatum and frontal cortex. Studies suggest that the BLA is involved in drug dependence and in the reinforcing actions of ethanol. For example, acute exposure to ethanol reduces anxiety, while withdrawal from chronic ethanol exposure alters BLA synaptic transmission, which increases anxiety, a common underlying cause of relapse. Exposure to and withdrawal from chronic alcohol also disrupts many brain areas that connect with the BLA. Despite these important findings, the acute actions of alcohol on the intrinsic excitability of BLA neurons have not been fully characterized. Methods: Brain slices containing the BLA were prepared from adult C57BL/6J male mice. Whole‐cell and sharp electrode electrophysiological recordings were performed to characterize the effects of acute ethanol on BLA neuronal and astrocyte function, respectively. Results: Ethanol inhibited action potential (AP) firing of BLA neurons but had no effect on BLA astrocyte resting membrane potential. The ethanol‐induced inhibition of firing was concentration‐dependent (11 to 66 mM) and accompanied by a reduction in the input resistance and an increase in the rheobase of BLA neurons. The inhibitory effect of ethanol was suppressed by picrotoxin, which blocks both γ‐aminobutyric acid type A (GABAA) and glycine receptors, but not by the selective glycine receptor antagonist strychnine, which suggests an involvement of GABAA receptors. Ethanol did not affect spontaneous inhibitory postsynaptic currents suggesting that the inhibition of BLA neuronal excitability by ethanol was not due to an increase in GABAA‐mediated synaptic transmission. However, acute ethanol enhanced the amplitude of the holding current of BLA neurons, an effect that was prevented by picrotoxin, which by itself reduced the holding current. Conclusions: These results suggest that BLA neurons express a GABA‐mediated tonic current that is enhanced by acute ethanol, which leads to reduced excitability of BLA neurons. [ABSTRACT FROM AUTHOR]
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- 2022
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38. Altered membrane properties but unchanged intrinsic excitability and spontaneous postsynaptic currents in an aged APPswe/PS1dE9 model of Alzheimer's disease.
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Ohline, Shane M., Xinhuai Liu, Ibrahim, Mohamed F., Mockett, Bruce M., Empson, Ruth M., Abraham, Wickliffe C., Iremonger, Karl J., and Jones, Peter P.
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ALZHEIMER'S disease ,PYRAMIDAL neurons ,AMYLOID plaque ,MOBILE apps ,LABORATORY mice ,ANIMAL models in research - Abstract
Neuronal hyperexcitability in Alzheimer's disease (AD) models is thought to either contribute to the formation of amyloid beta plaques or result from their formation. Neuronal hyperexcitability has been shown in the cerebral cortex of the widely used young APPswe/PS1dE9 mice, which have accelerated plaque formation. However, it is currently unclear if hyperexcitability also occurs in CA1 hippocampal neurons of aged animals in this model. In the present work, we have compared intrinsic excitability and spontaneous synaptic inputs from CA1 pyramidal cells of 8-month-old APPswe/PS1dE9 and wildtype control mice. We find no change in intrinsic excitability or spontaneous postsynaptic currents (PSCs) between groups. We did, however, find a reduced input resistance and an increase in hyperpolarization-activated sag current. These results are consistent with findings from other aged AD model mice, including the widely used 5xFAD and 3xTg. Together these results suggest that neuronal hyperexcitability is not a consistent feature of all AD mouse models, particularly at advanced ages. [ABSTRACT FROM AUTHOR]
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- 2022
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39. Altered membrane properties but unchanged intrinsic excitability and spontaneous postsynaptic currents in an aged APPswe/PS1dE9 model of Alzheimer’s disease
- Author
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Shane M. Ohline, Xinhuai Liu, Mohamed F. Ibrahim, Bruce M. Mockett, Ruth M. Empson, Wickliffe C. Abraham, Karl J. Iremonger, and Peter P. Jones
- Subjects
Alzheimer’s disease ,intrinsic excitability ,aging ,APP/PS1 double transgenic AD mouse ,postsynaptic currents ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Neuronal hyperexcitability in Alzheimer’s disease (AD) models is thought to either contribute to the formation of amyloid beta plaques or result from their formation. Neuronal hyperexcitability has been shown in the cerebral cortex of the widely used young APPswe/PS1dE9 mice, which have accelerated plaque formation. However, it is currently unclear if hyperexcitability also occurs in CA1 hippocampal neurons of aged animals in this model. In the present work, we have compared intrinsic excitability and spontaneous synaptic inputs from CA1 pyramidal cells of 8-month-old APPswe/PS1dE9 and wildtype control mice. We find no change in intrinsic excitability or spontaneous postsynaptic currents (PSCs) between groups. We did, however, find a reduced input resistance and an increase in hyperpolarization-activated sag current. These results are consistent with findings from other aged AD model mice, including the widely used 5xFAD and 3xTg. Together these results suggest that neuronal hyperexcitability is not a consistent feature of all AD mouse models, particularly at advanced ages.
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- 2022
- Full Text
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40. Corticotropin Releasing Factor Mediates KCa3.1 Inhibition, Hyperexcitability, and Seizures in Acquired Epilepsy.
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Tiwari, Manindra Nath, Mohan, Sandesh, Biala, Yoav, Shor, Oded, Benninger, Felix, and Yaari, Yoel
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CORTICOTROPIN releasing hormone , *PARTIAL epilepsy , *TEMPORAL lobe epilepsy , *EPILEPSY , *SEIZURES (Medicine) , *PROTEIN kinases , *CYCLIC-AMP-dependent protein kinase - Abstract
Temporal lobe epilepsy (TLE), the most common focal seizure disorder in adults, can be instigated in experimental animals by convulsant-induced status epilepticus (SE). Principal hippocampal neurons from SE-experienced epileptic male rats (postSE neurons) display markedly augmented spike output compared with neurons from nonepileptic animals (non-SE neurons). This enhanced firing results from a cAMP-dependent protein kinase A-mediated inhibition of KCa3.1, a subclass of Ca2+- gated K+ channels generating the slow afterhyperpolarizing Ca2+-gated K+ current (IsAHP). The inhibition of KCa3.1 in post-SE neurons leads to a marked reduction in amplitude of the IsAHP that evolves during repetitive firing, as well as in amplitude of the associated Ca2+-dependent component of the slow afterhyperpolarization potential (KCa-sAHP). Here we show that KCa3.1 inhibition in post-SE neurons is induced by corticotropin releasing factor (CRF) through its Type 1 receptor (CRF1R). Acute application of CRF1R antagonists restores KCa3.1 activity in post-SE neurons, normalizing KCa-sAHP/IsAHP amplitudes and neuronal spike output, without affecting these variables in non-SE neurons. Moreover, pharmacological antagonism of CRF1Rs in vivo reduces the frequency of spontaneous recurrent seizures in post-SE chronically epileptic rats. These findings may provide a new vista for treating TLE. [ABSTRACT FROM AUTHOR]
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- 2022
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41. Dominant role of adult neurogenesis‐induced structural heterogeneities in driving plasticity heterogeneity in dentate gyrus granule cells.
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Shridhar, Sameera, Mishra, Poonam, and Narayanan, Rishikesh
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GRANULE cells , *DENTATE gyrus , *HETEROGENEITY , *NEUROPLASTICITY , *RESOURCE allocation - Abstract
Neurons and synapses manifest pronounced variability in the amount of plasticity induced by identical activity patterns. The mechanisms underlying such plasticity heterogeneity, which have been implicated in context‐specific resource allocation during encoding, have remained unexplored. Here, we employed a systematic physiologically constrained parametric search to identify the cellular mechanisms behind plasticity heterogeneity in dentate gyrus granule cells. We used heterogeneous model populations to ensure that our conclusions were not biased by parametric choices in a single hand‐tuned model. We found that each of intrinsic, synaptic, and structural heterogeneities independently yielded heterogeneities in synaptic plasticity profiles obtained with two different induction protocols. However, among the disparate forms of neural‐circuit heterogeneities, our analyses demonstrated the dominance of neurogenesis‐induced structural heterogeneities in driving plasticity heterogeneity in granule cells. We found that strong relationships between neuronal intrinsic excitability and plasticity emerged only when adult neurogenesis‐induced heterogeneities in neural structure were accounted for. Importantly, our analyses showed that it was not imperative that the manifestation of neural‐circuit heterogeneities must translate to heterogeneities in plasticity profiles. Specifically, despite the expression of heterogeneities in structural, synaptic, and intrinsic neuronal properties, similar plasticity profiles were attainable across all models through synergistic interactions among these heterogeneities. We assessed the parametric combinations required for the manifestation of such degeneracy in the expression of plasticity profiles. We found that immature cells showed physiological plasticity profiles despite receiving afferent inputs with weak synaptic strengths. Thus, the high intrinsic excitability of immature granule cells was sufficient to counterbalance their low excitatory drive in the expression of plasticity profile degeneracy. Together, our analyses demonstrate that disparate forms of neural‐circuit heterogeneities could mechanistically drive plasticity heterogeneity, but also caution against treating neural‐circuit heterogeneities as proxies for plasticity heterogeneity. Our study emphasizes the need for quantitatively characterizing the relationship between neural‐circuit and plasticity heterogeneities across brain regions. [ABSTRACT FROM AUTHOR]
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- 2022
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42. Are Dendrites Conceptually Useful?
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Larkum, Matthew E.
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DENDRITES , *NEURONS - Abstract
• A manifesto for explaining the relevance of single-cell computation in brains and neural networks. • New examples principles of single-cell computation derived from dendritic properties. • Outline of the necessity to ground higher level concepts in robust implementation-level details. This article presents the argument that, while understanding the brain will require a multi-level approach, there is nevertheless something fundamental about understanding the components of the brain. I argue here that the standard description of neurons is not merely too simplistic, but also misses the true nature of how they operate at the computational level. In particular, the humble point neuron, devoid of dendrites with their powerful computational properties, prevents conceptual progress at higher levels of understanding. [ABSTRACT FROM AUTHOR]
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- 2022
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43. Activation of histamine type 2 receptors enhances intrinsic excitability of medium spiny neurons in the nucleus accumbens.
- Author
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Aceto, Giuseppe, Nardella, Luca, Nanni, Simona, Pecci, Valeria, Bertozzi, Alessia, Colussi, Claudia, D'Ascenzo, Marcello, and Grassi, Claudio
- Subjects
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NUCLEUS accumbens , *ACTION potentials , *HISTAMINE , *CYCLIC adenylic acid , *HISTAMINE receptors , *PROTEIN kinases , *PYRAMIDAL neurons , *INTERFERON receptors - Abstract
Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, from where they project to many brain areas including the nucleus accumbens (NAc), a brain area that integrates diverse monoaminergic inputs to coordinate motivated behaviours. While the NAc expresses various histamine receptor subtypes, the mechanisms by which histamine modulates NAc activity are still poorly understood. Using whole‐cell patch‐clamp recordings, we found that pharmacological activation of histamine 2 (H2) receptors elevates the excitability of NAc medium spiny neurons (MSNs), while activation of H1 receptors failed to significantly affect MSN excitability. The evoked firing of MSNs increased after seconds of local H2 agonist administration and remained elevated for minutes. H2 receptor (H2R) activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential afterhyperpolarization and increased the action potential half‐width. The increased excitability was protein kinase A‐dependent and associated with decreased A‐type K+ currents. In addition, selective pharmacological inhibition of the Kv4.2 channel, the main molecular determinant of A‐type K+ currents in MSNs, mimicked and occluded the increased excitability induced by H2R activation. Our results indicate that histaminergic transmission in the NAc increases MSN intrinsic excitability through H2R‐dependent modulation of Kv4.2 channels. Activation of H2R will significantly alter spike firing in MSNs in vivo, and this effect could be an important mechanism by which these receptors mediate certain aspects of goal‐induced behaviours. Key points: Histamine is synthesized and released by hypothalamic neurons of the tuberomammillary nucleus and serves as a general modulator for whole‐brain activity including the nucleus accumbens.Histamine receptors type 2 (HR2), which are expressed in the nucleus accumbens, couple to Gαs/off proteins which elevate cyclic adenosine monophosphate levels and activate protein kinase A.Whole‐cell patch‐clamp recordings revealed that H2R activation increased the evoked firing in medium spiny neurons of the nucleus accumbens via protein kinase A‐dependent mechanisms.HR2 activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential medium after‐hyperpolarization and increased the action potential half‐width. HR2 activation also reduced A‐type potassium current.Selective pharmacological inhibition of the Kv4.2 channel mimicked and occluded the increased excitability induced by H2R activation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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44. Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation
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Kyung-Ran Kim, Yoonsub Kim, Hyeon-Ju Jeong, Jong-Sun Kang, Sang Hun Lee, Yujin Kim, Suk-Ho Lee, and Won-Kyung Ho
- Subjects
Tg2676 ,Intrinsic excitability ,Dentate gyrus ,Kv4.1 ,Alzheimer’s disease ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes memory loss. Most AD researches have focused on neurodegeneration mechanisms. Considering that neurodegenerative changes are not reversible, understanding early functional changes before neurodegeneration is critical to develop new strategies for early detection and treatment of AD. We found that Tg2576 mice exhibited impaired pattern separation at the early preclinical stage. Based on previous studies suggesting a critical role of dentate gyrus (DG) in pattern separation, we investigated functional changes in DG of Tg2576 mice. We found that granule cells in DG (DG-GCs) in Tg2576 mice showed increased action potential firing in response to long depolarizations and reduced 4-AP sensitive K+-currents compared to DG-GCs in wild-type (WT) mice. Among Kv4 family channels, Kv4.1 mRNA expression in DG was significantly lower in Tg2576 mice. We confirmed that Kv4.1 protein expression was reduced in Tg2576, and this reduction was restored by antioxidant treatment. Hyperexcitable DG and impaired pattern separation in Tg2576 mice were also recovered by antioxidant treatment. These results highlight the hyperexcitability of DG-GCs as a pathophysiologic mechanism underlying early cognitive deficits in AD and Kv4.1 as a new target for AD pathogenesis in relation to increased oxidative stress.
- Published
- 2021
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45. Transient ultrasound stimulation has lasting effects on neuronal excitability
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Benjamin Clennell, Tom G.J. Steward, Meg Elley, Eunju Shin, Miles Weston, Bruce W. Drinkwater, and Daniel J. Whitcomb
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Ultrasound stimulation ,Neuromodulation ,Intrinsic excitability ,Primary neuron ,Whole-cell patch clamp ,Electron microscopy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Background: Transcranial ultrasound stimulation can acutely modulate brain activity, but the lasting effects on neurons are unknown. Objective: To assess the excitability profile of neurons in the hours following transient ultrasound stimulation. Methods: Primary rat cortical neurons were stimulated with a 40 s, 200 kHz pulsed ultrasound stimulation or sham-stimulation. Intrinsic firing properties were investigated through whole-cell patch-clamp recording by evoking action potentials in response to somatic current injection. Recordings were taken at set timepoints following ultrasound stimulation: 0–2 h, 6–8 h, 12–14 h and 24–26 h. Transmission electron microscopy was used to assess synaptic ultrastructure at the same timepoints. Results: In the 0–2 h window, neurons stimulated with ultrasound displayed an increase in the mean frequency of evoked action potentials of 32% above control cell levels (p = 0.023). After 4–6 h this increase was measured as 44% (p = 0.0043). By 12–14 h this effect was eliminated and remained absent 24–26 h post-stimulation. These changes to action potential firing occurred in conjunction with statistically significant differences between control and ultrasound-stimulated neurons in action potential half-width, depolarisation rate, and repolarisation rate, that were similarly eliminated by 24 h following stimulation. These effects occurred in the absence of alterations to intrinsic membrane properties or synaptic ultrastructure. Conclusion: We report that stimulating neurons with 40 s of ultrasound enhances their excitability for up to 8 h in conjunction with modifications to action potential kinetics. This occurs in the absence of major ultrastructural change or modification of intrinsic membrane properties. These results can inform the application of transcranial ultrasound in experimental and therapeutic settings.
- Published
- 2021
- Full Text
- View/download PDF
46. Immune-Triggered Forms of Plasticity Across Brain Regions
- Author
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Momoka Hikosaka, Takeo Kawano, Yayoi Wada, Tomoki Maeda, Takeshi Sakurai, and Gen Ohtsuki
- Subjects
immune-triggered plasticity ,brain immune cells ,inflammatory mediators ,synaptic transmission ,intrinsic excitability ,cerebellum ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Immune cells play numerous roles in the host defense against the invasion of microorganisms and pathogens, which induces the release of inflammatory mediators (e.g., cytokines and chemokines). In the CNS, microglia is the major resident immune cell. Recent efforts have revealed the diversity of the cell types and the heterogeneity of their functions. The refinement of the synapse structure was a hallmark feature of the microglia, while they are also involved in the myelination and capillary dynamics. Another promising feature is the modulation of the synaptic transmission as synaptic plasticity and the intrinsic excitability of neurons as non-synaptic plasticity. Those modulations of physiological properties of neurons are considered induced by both transient and chronic exposures to inflammatory mediators, which cause behavioral disorders seen in mental illness. It is plausible for astrocytes and pericytes other than microglia and macrophage to induce the immune-triggered plasticity of neurons. However, current understanding has yet achieved to unveil what inflammatory mediators from what immune cells or glia induce a form of plasticity modulating pre-, post-synaptic functions and intrinsic excitability of neurons. It is still unclear what ion channels and intracellular signaling of what types of neurons in which brain regions of the CNS are involved. In this review, we introduce the ubiquitous modulation of the synaptic efficacy and the intrinsic excitability across the brain by immune cells and related inflammatory cytokines with the mechanism for induction. Specifically, we compare neuro-modulation mechanisms by microglia of the intrinsic excitability of cerebellar Purkinje neurons with cerebral pyramidal neurons, stressing the inverted directionality of the plasticity. We also discuss the suppression and augmentation of the extent of plasticity by inflammatory mediators, as the meta-plasticity by immunity. Lastly, we sum up forms of immune-triggered plasticity in the different brain regions with disease relevance. Together, brain immunity influences our cognition, sense, memory, and behavior via immune-triggered plasticity.
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- 2022
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47. Intrinsic excitability mechanisms of neuronal ensemble formation
- Author
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Tzitzitlini Alejandre-García, Samuel Kim, Jesús Pérez-Ortega, and Rafael Yuste
- Subjects
ensembles ,intrinsic excitability ,optogenetics ,visual cortex ,Hebbian plasticity ,synaptic connection ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Neuronal ensembles are coactive groups of cortical neurons, found in spontaneous and evoked activity, that can mediate perception and behavior. To understand the mechanisms that lead to the formation of ensembles, we co-activated layer 2/3 pyramidal neurons in brain slices from mouse visual cortex, in animals of both sexes, replicating in vitro an optogenetic protocol to generate ensembles in vivo. Using whole-cell and perforated patch-clamp pair recordings we found that, after optogenetic or electrical stimulation, coactivated neurons increased their correlated activity, a hallmark of ensemble formation. Coactivated neurons showed small biphasic changes in presynaptic plasticity, with an initial depression followed by a potentiation after a recovery period. Optogenetic and electrical stimulation also induced significant increases in frequency and amplitude of spontaneous EPSPs, even after single-cell stimulation. In addition, we observed unexpected strong and persistent increases in neuronal excitability after stimulation, with increases in membrane resistance and reductions in spike threshold. A pharmacological agent that blocks changes in membrane resistance reverted this effect. These significant increases in excitability can explain the observed biphasic synaptic plasticity. We conclude that cell-intrinsic changes in excitability are involved in the formation of neuronal ensembles. We propose an ‘iceberg’ model, by which increased neuronal excitability makes subthreshold connections suprathreshold, enhancing the effect of already existing synapses, and generating a new neuronal ensemble.
- Published
- 2022
- Full Text
- View/download PDF
48. Sex differences in mouse infralimbic cortex projections to the nucleus accumbens shell
- Author
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Johnson, Caroline S., Chapp, Andrew D., Lind, Erin B., Thomas, Mark J., and Mermelstein, Paul G.
- Published
- 2023
- Full Text
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49. Activation of D1/D5 receptors ameliorates decreased intrinsic excitability of hippocampal neurons induced by neonatal blockade of N‐methyl‐d‐aspartate receptors.
- Author
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Griego, Ernesto, Hernández‐Frausto, Melissa, Márquez, Luis A., Lara‐Valderrabano, Leonardo, López Rubalcava, Carolina, and Galván, Emilio J.
- Subjects
- *
NEURONS , *HIPPOCAMPUS (Brain) , *MAZE tests , *METHYL aspartate receptors , *SALINE solutions , *COGNITIVE ability , *PYRAMIDAL neurons , *DOPAMINERGIC neurons - Abstract
Background and Purpose: Dysregulation of dopaminergic transmission combined with transient hypofunction of N‐methyl‐d‐aspartate receptors (NMDARs) is a key mechanism that may underlie cognitive symptoms of schizophrenia. Experimental Approach Therefore, we aimed to identify electrophysiologic alterations in animals neonatally treated with the NMDA receptor antagonist, MK‐801, or with saline solution. Key Results: Patch‐clamp whole‐cell recordings from MK‐801‐treated animals revealed altered passive and active electrophysiologic properties compared with CA1 pyramidal cells from saline‐treated animals, including up‐regulation of the K+ inward‐rectifier conductance and fast‐inactivating and slow/non‐inactivating K+ currents. Up‐regulation of these membrane ionic currents reduced the overall excitability and altered the firing properties of CA1 pyramidal cells. We also explored the capability of cells treated with MK‐801 to express intrinsic excitability potentiation, a non‐synaptic form of hippocampal plasticity associated with cognition and memory formation. CA1 pyramidal cells from animals treated with MK‐801 were unable to convey intrinsic excitability potentiation and had blunted synaptic potentiation. Furthermore, MK‐801‐treated animals also exhibited reduced cognitive performance in the Barnes maze task. Notably, activation of D1/D5 receptors with SKF‐38,393 partially restored electrophysiologic alterations caused by neonatal treatment with MK‐801. Conclusion and Implications: Our results offer a molecular and mechanistic explanation based on dysregulation of glutamatergic transmission, in addition to dopaminergic transmission, that may contribute to the understanding of the cognitive deterioration associated with schizophrenia. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
50. Decreased intrinsic excitability of cerebellar Purkinje cells following optokinetic learning in mice
- Author
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Yong Gyu Kim and Sang Jeong Kim
- Subjects
Intrinsic excitability ,Cerebellum ,Purkinje cell ,Oculomotor learning ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract The optokinetic response (OKR), a reflexive eye movement evoked by a motion of the visual field, is known to adapt its strength to cope with an environmental change throughout life, which is a type of cerebellum-dependent learning. Previous studies suggested that OKR learning induces changes in in-vivo spiking activity and synaptic transmission of the cerebellar Purkinje cell (PC). Despite the recent emphasis on the importance of the intrinsic excitability related to learning and memory, the direct correlation between the intrinsic excitability of PCs and OKR learning has not been tested. In the present study, by utilizing the whole-cell patch-clamp recording, we compared the responses of cerebellar PCs to somatic current injection between the control and learned groups. We found that the neurons from the learned group showed a significant reduction in mean firing rate compared with neurons in the control group. In the analysis of single action potential (AP), we revealed that the rheobase current for the generation of single AP was increased by OKR learning, while AP threshold, AP amplitude, and afterhyperpolarization amplitude were not altered. Taken together, our result suggests that the decrease in the intrinsic excitability was induced in the cerebellar PC of learned group by an increase in the current threshold for generating AP.
- Published
- 2020
- Full Text
- View/download PDF
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