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Nociceptive information is transmitted by action potentials (APs) through primary afferent neurons from the periphery to the central nervous system. Voltage-gated Na+ channels are involved in this AP production, while transient receptor potential (TRP) channels, which are non-selective cation channels, are involved in receiving and transmitting nociceptive stimuli in the peripheral and central terminals of the primary afferent neurons. Peripheral terminal TRP vanilloid-1 (TRPV1), ankylin-1 (TRPA1) and melastatin-8 (TRPM8) activation produces APs, while central terminal TRP activation enhances the spontaneous release of L-glutamate from the terminal to spinal cord and brain stem lamina II neurons that play a pivotal role in modulating nociceptive transmission. There is much evidence demonstrating that chemical compounds involved in Na+ channel (or nerve AP conduction) inhibition modify TRP channel functions. Among these compounds are local anesthetics, anti-epileptics, α2-adrenoceptor agonists, antidepressants (all of which are used as analgesic adjuvants), general anesthetics, opioids, non-steroidal anti-inflammatory drugs and plant-derived compounds, many of which are involved in antinociception. This review mentions the modulation of Na+ channels and TRP channels including TRPV1, TRPA1 and TRPM8, both of which modulations are produced by pain-related compounds. [ABSTRACT FROM AUTHOR]

Key points Basket cells are inhibitory interneurons in cortical structures with the potential to efficiently control the activity of their postsynaptic partners. Although their contribution to higher order cognitive functions associated with the medial prefrontal cortex (mPFC) relies on the characteristics of their synaptic connections, the way that they are embedded into local circuits is still not fully uncovered. Here, we determined the synaptic properties of excitatory and inhibitory connections between pyramidal neurons (PNs), cholecystokinin‐containing basket cells (CCKBCs) and parvalbumin‐containing basket cells (PVBCs) in the mouse mPFC. By performing paired recordings, we revealed that PVBCs receive larger unitary excitatory postsynaptic currents from PNs with shorter latency and faster kinetic properties compared to events evoked in CCKBCs. Also, unitary inhibitory postsynaptic currents in PNs were more reliably evoked by PVBCs than by CCKBCs, yet the former connections showed profound short‐term depression. Moreover, we demonstrated that CCKBCs and PVBCs in the mPFC are connected with each other. Because alterations in PVBC function have been linked to neurological and psychiatric conditions such as Alzheimer's disease and schizophrenia and CCKBC vulnerability might play a role in mood disorders, a deeper understanding of the general features of basket cell synapses could serve as a reference point for future investigations with therapeutic objectives. Cholecystokinin‐ (CCKBCs) and parvalbumin‐expressing basket cells (PVBCs) have distinct passive and active membrane properties. Pyramidal neurons give rise to larger unitary excitatory postsynaptic currents in PVBCs compared to events in CCKBCs. Unitary inhibitory postsynaptic currents in pyramidal neurons are more reliably evoked by PVBCs than by CCKBCs. Basket cells form chemical synapses and gap junctions with their own cell type. The two basket cell types are connected with each other. [ABSTRACT FROM AUTHOR]

α-Neurexins are essential and highly expressed presynaptic cell-adhesion molecules that are frequently linked to neuropsychiatric and neurodevelopmental disorders. Despite their importance, how the elaborate extracellular sequences of α-neurexins contribute to synapse function is poorly understood. We recently characterized the presynaptic gain-of-function phenotype caused by a missense mutation in an evolutionarily conserved extracellular sequence of neurexin-3α (A687T) that we identified in a patient diagnosed with profound intellectual disability and epilepsy. The striking A687T gain-of-function mutation on neurexin-3α prompted us to systematically test using mutants whether the presynaptic gain-of-function phenotype is a consequence of the addition of side-chain bulk (i.e., A687V) or polar/hydrophilic properties (i.e., A687S). We used multidisciplinary approaches in mixed-sex primary hippocampal cultures to assess the impact of the neurexin-3αA687 residue on synapse morphology, function and ligand binding. Unexpectedly, neither A687V nor A687S recapitulated the neurexin-3α A687T phenotype. Instead, distinct from A687T, molecular replacement with A687S significantly enhanced postsynaptic properties exclusively at excitatory synapses and selectively increased binding to neuroligin-1 and neuroligin-3 without changing binding to neuroligin-2 or LRRTM2. Importantly, we provide the first experimental evidence supporting the notion that the position A687 of neurexin-3α and the N-terminal sequences of neuroligins may contribute to the stability of α-neurexin--neuroligin-1 trans-synaptic interactions and that these interactions may specifically regulate the postsynaptic strength of excitatory synapses. [ABSTRACT FROM AUTHOR]

The most pronounced neuropathological feature of Parkinson's disease (PD) is the loss of dopamine (DA) neurons in the substantia nigra compacta (SNc), which depletes striatal DA. Hypothalamic oxytocin is found to be reduced in PD patients and closely interacts with the DA system, but the role of oxytocin in PD remains unclear. Here, the disturbances of endogenous oxytocin level and the substantia nigra (SN) oxytocin receptor expression in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse model is observed, correlated with the striatal tyrosine hydroxylase (TH) expression reduction. Killing/silencing hypothalamic oxytocin neurons aggravates the vulnerability of nigrostriatal DA signal to MPTP, whereas elevating oxytocin level by intranasal delivery or microinjecting into the SN promotes the resistance. In addition, knocking out SN oxytocin receptors induces the time‐dependent reductions of SNc DA neurons, striatal TH expression, and striatal DA level by increasing neuronal excitotoxicity. These results further uncover that oxytocin dampens the excitatory synaptic inputs onto DA neurons via activating oxytocin receptor‐expressed SN GABA neurons, which target GABA(B) receptors expressed in SNc DA neuron‐projecting glutamatergic axons, to reduce excitotoxicity. Thus, besides the well‐known prosocial effect, oxytocin acts as a key endogenous factor in protecting the nigrostriatal DA system. [ABSTRACT FROM AUTHOR]

Key points Along the ascending auditory pathway, there is a broad shift from temporal coding, which is common in the lower auditory brainstem, to rate coding, which predominates in auditory cortex. This temporal‐to‐rate transition is particularly prominent in the inferior colliculus (IC), the midbrain hub of the auditory system, but the mechanisms that govern how individual IC neurons integrate information across time remain largely unknown. Here, we report the widespread expression of Glun2c and Glun2d mRNA in IC neurons. GluN2C/D‐containing NMDA receptors are relatively insensitive to voltage‐dependent Mg2+ blockade, and thus can conduct current at resting membrane potential. Using in situ hybridization and pharmacology, we show that vasoactive intestinal peptide neurons in the IC express GluN2D‐containing NMDA receptors that are activatable by commissural inputs from the contralateral IC. In addition, GluN2C/D‐containing receptors have much slower kinetics than other NMDA receptors, and we found that GluN2D‐containing receptors facilitate temporal summation of synaptic inputs in vasoactive intestinal peptide neurons. In a model neuron, we show that a GluN2C/D‐like conductance interacts with the passive membrane properties of the neuron to alter temporal and rate coding of stimulus trains. Consistent with this, we show in vivo that blocking GluN2C/D‐containing receptors decreases both the spontaneous firing rate and the overall firing rate elicited by amplitude‐modulated sounds in many IC neurons. These results suggest that GluN2C/D‐containing NMDA receptors influence rate coding for auditory stimuli in the IC by facilitating the temporal integration of synaptic inputs. NMDA receptors are critical components of most glutamatergic circuits in the brain, and the diversity of NMDA receptor subtypes yields receptors with a variety of functions. We found that many neurons in the auditory midbrain express GluN2C and/or GluN2D NMDA receptor subunits, which are less sensitive to Mg2+ blockade than the more commonly expressed GluN2A/B subunits. We show that GluN2C/D‐containing receptors conducted current at resting membrane potential and enhanced temporal summation of synaptic inputs. In a model, we show that GluN2C/D‐containing receptors provide additive gain for input‐output functions driven by trains of synaptic inputs. In line with this, we found that blocking GluN2C/D‐containing NMDA receptors in vivo decreased both spontaneous firing rates and firing evoked by amplitude‐modulated sounds. [ABSTRACT FROM AUTHOR]

Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity that can precipitate stress‐related psychiatric disorders. We found that male mice after 8 weeks of adolescent social isolation (SI) have markedly increased aggression after being exposed to 2 h of restraint stress (RS), which was accompanied by a significant increase of AMPA receptor‐ and NMDA receptor‐mediated synaptic transmission in prefrontal cortex (PFC) pyramidal neurons of SIRS males. Compared to group‐housed counterparts, SIRS males exhibited a significantly decreased level of histone H3 acetylation in PFC. Systemic administration of class I histone deacetylase inhibitors, romidepsin or MS‐275, ameliorated the aggressive behaviour, as well as general social interaction deficits, of SIRS males. Electrophysiological recordings also found normalization of PFC glutamatergic currents by romidepsin treatment of SIRS male mice. These results revealed an epigenetic mechanism and intervention avenue for aggression induced by chronic social isolation. Key points: Adolescent chronic social isolation can precipitate stress‐related psychiatric disorders.A significant increase of glutamatergic transmission is found in the prefrontal cortex (PFC) of socially isolated male mice exposed to an acute stress (SIRS).Treatment with class I histone deacetylase (HDAC) inhibitors ameliorates the aggressive behaviour and social interaction deficits of SIRS males, and normalizes glutamatergic currents in PFC neurons.It provides an epigenetic mechanism and intervention avenue for aberrant stress responses induced by chronic social isolation. [ABSTRACT FROM AUTHOR]

Abstract Aim Excitatory projections from the prelimbic cortex (PL) to the basolateral nucleus of the amygdala (BLA) are implicated in the regulation of anxiety‐like behaviors, and we previously demonstrated that anxiolytic‐like effects of the selective delta‐opioid receptor (DOP) agonist KNT‐127 is involved in suppressing glutamate neurotransmission in the PL. Here, we investigated the mechanisms underlying the anxiolytic‐like effect of KNT‐127 in mice by combining optogenetic stimulation of the PL–BLA pathway with behavioral analyses. Methods Four‐week‐old male C57BL/6J mice received bilateral administration of adeno‐associated virus (AAV)2‐CaMKIIa‐hChR2(H134R)‐enhanced yellow fluorescent protein (EYFP) into the PL to induce expression of the light‐activated excitatory ionic channel ChR2. Subsequently, an optic fiber cannula connected to a wireless photo‐stimulator was implanted into the BLA for optogenetic PL–BLA pathway stimulation. We evaluated innate anxiety using the elevated plus maze (EPM) and open field (OF) tests as well as learned anxiety using the contextual fear conditioning (CFC) test. Results Optogenetic activation of the PL–BLA pathway enhanced anxiety‐like behaviors in the EPM and OF, while prior subcutaneous administration of KNT‐127 (10 mg/kg) reduced this anxiogenic effect. In contrast, optogenetic activation of the PL–BLA pathway had no significant effect on conditioned fear. Conclusion Our findings indicate that the PL–BLA circuit contributes to innate anxiety and that the anxiolytic‐like effects of KNT‐127 are mediated at least in part by suppression of PL–BLA transmission. The PL delta‐opioid receptor may thus be an effective therapeutic target for anxiety disorders.

Aim: Excitatory projections from the prelimbic cortex (PL) to the basolateral nucleus of the amygdala (BLA) are implicated in the regulation of anxiety‐like behaviors, and we previously demonstrated that anxiolytic‐like effects of the selective delta‐opioid receptor (DOP) agonist KNT‐127 is involved in suppressing glutamate neurotransmission in the PL. Here, we investigated the mechanisms underlying the anxiolytic‐like effect of KNT‐127 in mice by combining optogenetic stimulation of the PL–BLA pathway with behavioral analyses. Methods: Four‐week‐old male C57BL/6J mice received bilateral administration of adeno‐associated virus (AAV)2‐CaMKIIa‐hChR2(H134R)‐enhanced yellow fluorescent protein (EYFP) into the PL to induce expression of the light‐activated excitatory ionic channel ChR2. Subsequently, an optic fiber cannula connected to a wireless photo‐stimulator was implanted into the BLA for optogenetic PL–BLA pathway stimulation. We evaluated innate anxiety using the elevated plus maze (EPM) and open field (OF) tests as well as learned anxiety using the contextual fear conditioning (CFC) test. Results: Optogenetic activation of the PL–BLA pathway enhanced anxiety‐like behaviors in the EPM and OF, while prior subcutaneous administration of KNT‐127 (10 mg/kg) reduced this anxiogenic effect. In contrast, optogenetic activation of the PL–BLA pathway had no significant effect on conditioned fear. Conclusion: Our findings indicate that the PL–BLA circuit contributes to innate anxiety and that the anxiolytic‐like effects of KNT‐127 are mediated at least in part by suppression of PL–BLA transmission. The PL delta‐opioid receptor may thus be an effective therapeutic target for anxiety disorders. [ABSTRACT FROM AUTHOR]

Summary: Background: Schizophrenia, a debilitating psychiatric disorder, displays considerable interindividual variation in clinical presentations. The ongoing debate revolves around whether this heterogeneity signifies a continuum of severity linked to a singular causative factor or a collection of distinct subtypes with unique origins. Within the realm of schizophrenia, the functional impairment of GluN2A, a subtype of the NMDA receptor, has been associated with an elevated risk. Despite GluN2A’s expression across various neuronal types throughout the brain, its specific contributions to schizophrenia and its involvement in particular cell types or brain regions remain unexplored. Methods: We generated age-specific, cell type-specific or brain region-specific conditional knockout mice targeting GluN2A and conducted a comprehensive analysis using tests measuring phenotypes relevant to schizophrenia. Findings: Through the induction of germline ablation of GluN2A, we observed the emergence of numerous schizophrenia-associated abnormalities in adult mice. Intriguingly, GluN2A knockout performed at different ages, in specific cell types and within distinct brain regions, we observed overlapping yet distinct schizophrenia-related phenotypes in mice. Interpretation: Our interpretation suggests that the dysfunction of GluN2A is sufficient to evoke heterogeneous manifestations associated with schizophrenia, indicating that GluN2A stands as a prominent risk factor and a potential therapeutic target for schizophrenia. Funding: This project received support from the Shanghai Municipal Science and Technology Major Project (Grant No. 2019SHZDZX02) awarded to Y.C. and the Natural Science Foundation of Shanghai (Grant No. 19ZR1468600 and 201409003800) awarded to G.Y.

Introduction: Annexin A2 (ANXA2) participates in the pathology of a variety of diseases. Nevertheless, the impact of ANXA2 on epilepsy remains to be clarified. Aims: Hence, the study aimed at investigating the underlying role of ANXA2 in epilepsy through behavioral, electrophysiological, and pathological analyses. Results: It was found that ANXA2 was markedly upregulated in the cortical tissues of temporal lobe epilepsy patients (TLE), kainic acid (KA)‐induced epilepsy mice, and in a seizure‐like model in vitro. ANXA2 silencing in mice suppressed first seizure latency, number of seizures, and seizure duration in behavioral analysis. In addition, abnormal brain discharges were less frequent and shorter in the hippocampal local field potential (LFP) record. Furthermore, the results showed that the frequency of miniature excitatory postsynaptic currents was decreased in ANXA2 knockdown mice, indicating that the excitatory synaptic transmission is reduced. Co‐immunoprecipitation (COIP) experiments demonstrated that ANXA2 interacted with the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) subunit GluA1. Moreover, ANXA2 knockdown decreased GluA1 expression on the cell surface and its phosphorylation onserine 831 and serine 845, related to the decreased phosphorylation levels mediated by protein kinases A and C (PKA and PKC). Conclusions: This study covers a previously unknown and key function of ANXA2 in epilepsy. These findings indicate that ANXA2 can regulate excitatory synaptic activity mediated by AMPAR subunit GluA1 to improve seizure activity, which can provide novel insights for the treatment and prevention of epilepsy. [ABSTRACT FROM AUTHOR]

Background Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder with an enormous socioeconomic burden. Opioid overdose deaths have reached an epidemic level, especially for fentanyl. One of the biggest challenges to treat OUD is the relapse to drug seeking after prolonged abstinence. Abnormalities in insulin-like growth factor-1 (IGF-1) have been reported in various neurological and psychiatric disorders, including OUD. However, whether IGF-1 and its downstream signaling pathways are associated with relapse to fentanyl seeking remains unclear. Methods Mice were subjected to daily 2-hour fentanyl (10 μg/mL, 27 μL/infusion) oral self-administration training for 14 days, followed by 14-day fentanyl cessation. Expression levels of IGF-1/IGF-1 receptor and downstream signaling pathways in the dorsomedial prefrontal cortex (dmPFC) were detected. Then, IGF-1 was bilaterally microinjected into the dmPFC from fentanyl cessation day 9 to day 13. Fentanyl-seeking behavior and excitatory synaptic transmission of pyramidal neurons in PFC were evaluated. Results We found that 14-day cessation from fentanyl oral self-administration caused significant downregulation of IGF-1 and IGF-1 receptor phosphorylation in the dmPFC. These changes were accompanied by inhibition of the downstream Akt and S6 signaling pathway. In addition, local administration of IGF-1 in the dmPFC attenuated context-induced fentanyl-seeking behavior. Furthermore, electrophysiology and immunohistochemistry analyses showed that IGF-1 blocked fentanyl-induced reduction of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors-mediated excitatory synaptic transmission as well as synaptic expression of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and N-methyl-D-aspartate receptor subunits. Conclusions These results suggest that IGF-1 in the PFC plays a pivotal role in regulating fentanyl seeking after prolonged cessation from fentanyl oral self-administration. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the serotonergic (5-HT) system in the amygdala has significant effects on affective states. Dysregulation of the 5-HT system in the basolateral amygdaloid complex causes affective disorders. To search for therapeutic targets, subtype specification of 5-HT receptors is crucial. The present study was undertaken to identify the 5-HT receptor subtype responsible for the 5-HT-mediated suppression of excitatory transmission to principal neurons (PNs) in the lateral amygdala (LA). Whole-cell recordings were performed to record excitatory post synaptic currents (EPSCs) in acute rat brain slices. We confirmed that 5-HT and α-m-5-HT, a broad 5-HT 2 receptor agonist, attenuated EPSCs in LA PNs. The extent of suppressions by 5-HT and α-m-5-HT remained unchanged in the presence of ritanserin, a broad 5-HT 2 receptor antagonist. In the presence of NAS-181, a selective 5-HT 1B receptor antagonist, the extent of EPSC suppressions by 5-HT and α-m-5-HT was diminished. CP93129, a selective 5-HT 1B receptor agonist, attenuated EPSCs in LA PNs, and this effect was abolished in the presence of NAS-181. Additionally, the paired-pulse ratio of EPSCs was increased by CP93129. Thus, our results indicate that 5-HT and α-m-5-HT attenuate excitatory transmissions to LA PNs via presynaptic 5-HT 1B receptors. • 5-HT and α-m-5HT attenuate excitatory synaptic inputs to principal neurons in the lateral amygdala via 5-HT 1B receptors. • Activation of the presynaptic 5-HT 1B receptors attenuates excitatory synaptic transmissions. • α-m-5HT, regarded as a broad 5-HT 2 receptor agonist, acts as a 5-HT 1B agonist at the range of normally used concentration. [ABSTRACT FROM AUTHOR]

The hippocampus exerts inhibitory feedback on the release of glucocorticoids. Because the major hippocampal efferent projections are excitatory, it has been hypothesized that this inhibition is mediated by populations of inhibitory neurons in the hypothalamus or elsewhere. These regions would be excited by hippocampal efferents and project to corticotropin-releasing factor (CRF) cells in the paraventricular nucleus of the hypothalamus (PVN). A direct demonstration of the synaptic responses elicited by hippocampal outputs in PVN cells or upstream GABAergic interneurons has not been provided previously. Here, we used viral vectors to express channelrhodopsin (ChR) and enhanced yellow fluorescent protein (EYFP) in pyramidal cells in the ventral hippocampus (vHip) in mice expressing tdTomato in GABA- or CRF-expressing neurons. We observed dense innervation of the bed nucleus of the stria terminalis (BNST) by labeled vHip axons and sparse labeling within the PVN. Using whole-cell voltage-clamp recording in parasagittal brain slices containing the BNST and PVN, photostimulation of vHip terminals elicited rapid excitatory postsynaptic currents (EPSCs) and longer-latency inhibitory postsynaptic currents (IPSCs) in both CRF+ and GAD + cells. The ratio of synaptic excitation and inhibition was maintained in CRF + cells during 20 Hz stimulus trains. Photostimulation of hippocampal afferents to the BNST and PVN in vivo inhibited the rise in blood glucocorticoid levels produced by acute restraint stress. We thus provide functional evidence suggesting that hippocampal output to the BNST contributes to a net inhibition of the hypothalamic-pituitary axis, providing further mechanistic insights into this process using methods with enhanced spatial and temporal resolution.

Epilepsy is a common disease of the nervous system. Autophagy is a degradation process involved in epilepsy, and in turn, seizures can activate autophagy. Beclin1 plays a critical role in autophagy and participates in numerous physiological and pathological processes. However, the mechanism underlying the effect of Beclin1 on epilepsy remains unclear. In this study, we detected increased expression of Beclin1 in brain tissues from patients with temporal lobe epilepsy (TLE). Heterozygous disruption of beclin1 decreased susceptibility to epilepsy and suppressed seizure activity in two mouse epilepsy models. We further illustrated for the first time that heterozygous disruption of beclin1 suppresses excitatory synaptic transmission, which may be caused by a decreased dendritic spine density. These findings suggest for the first time that the regulation of Beclin1 may serve as a strategy for antiepileptic therapy. In addition, Beclin1 participates in synaptic transmission, and the development of dendritic spines may be a biological function of Beclin1 independent of its role in autophagy. [ABSTRACT FROM AUTHOR]

Astrocytes, comprising the primary glial-cell type, are involved in the formation and maturation of synapses, and thus contribute to sustainable synaptic transmission between neurons. Given that the animals in higher phylogenetic tree have brains with a higher density of glial cells with respect to neurons, there is a possibility that the relative astrocytic density directly influences synaptic transmission. However, the notion has not been tested thoroughly. Here we addressed it, by using a primary culture preparation where single hippocampal neurons are surrounded by a variable but a countable number of cortical astrocytes in dot-patterned microislands, and recording synaptic transmission by patch-clamp electrophysiology. Neurons with a higher astrocytic density showed a higher amplitude of the evoked excitatory postsynaptic current than that of neurons with a lower astrocytic density. The size of the readily releasable pool of synaptic vesicles per neuron was significantly larger. The frequency of spontaneous synaptic transmission was higher, but the amplitude was unchanged. The number of morphologically identified glutamatergic synapses was comparable, but the percentage of functional ones was increased, indicating a lower ratio of presynaptically silent synapses. Taken together, the higher astrocytic density enhanced excitatory synaptic transmission by increasing the fraction of functional synapses through presynaptic un-silencing.

Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer’s disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in slices from mice brainstem. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10–20 µM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased MT-bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin 1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission.

Repetitive synaptic stimulation can induce different forms of synaptic plasticity but may also limit the robustness of synaptic transmission by exhausting key resources. Little is known about how synaptic transmission is stabilized after high-frequency stimulation. In the present study, we observed that tetanic stimulation of the Drosophila neuromuscular junction (NMJ) decreases quantal content, release-ready vesicle pool size and synaptic vesicle density for minutes after stimulation. This was accompanied by a pronounced increase in quantal size. Interestingly, action potential-evoked synaptic transmission remained largely unchanged. EPSC amplitude fluctuation analysis confirmed the post-tetanic increase in quantal size and the decrease in quantal content, suggesting that the quantal size increase counteracts release depression to maintain evoked transmission. The magnitude of the post-tetanic quantal size increase and release depression correlated with stimulation frequency and duration, indicating activity-dependent stabilization of synaptic transmission. The post-tetanic quantal size increase persisted after genetic ablation of the glutamate receptor subunits GluRIIA or GluRIIB, and glutamate receptor calcium permeability, as well as blockade of postsynaptic calcium channels. By contrast, it was strongly attenuated by pharmacological or presynaptic genetic perturbation of the GTPase dynamin. Similar observations were made after inhibition of the H + -ATPase, suggesting that the quantal size increase is presynaptically driven. Additionally, dynamin and H + -ATPase perturbation resulted in a post-tetanic decrease in evoked amplitudes. Finally, we observed an increase in synaptic vesicle diameter after tetanic stimulation. Thus, a presynaptically-driven quantal size increase, likely mediated by larger synaptic vesicles, counterbalances post-tetanic release depression, thereby conferring robustness to synaptic transmission on the minute time scale. KEY POINTS: Many synapses transmit robustly after sustained activity despite the limitation of key resources, such as release-ready synaptic vesicles. We report robust synaptic transmission after sustained high-frequency stimulation of the Drosophila neuromuscular junction despite a reduction in release-ready vesicle number. An increased postsynaptic response to individual vesicles, likely driven by an increase in vesicle size due to endocytosis defects, stabilizes synaptic efficacy for minutes after sustained activity. Our study provides novel insights into the mechanisms governing synaptic stability after sustained neural activity., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Abstract Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. This study was designed to examine the role of anterior insular cortex (aIC) in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). Abdomen hyperalgesia and anxiety were assessed by von Frey filament and open field tests, respectively. Two weeks after surgery, the activation of aIC was indicated by FOS immunohistochemical staining and electrophysiological recordings. Expressions of VGluT1, NMDAR subunit NR2B and AMPAR subunit GluR1 were analyzed by immunoblottings. The regulatory roles of aIC in hyperalgesia and pain-related anxiety were detected via pharmacological approach and chemogenetics in CP rats. Our results showed that TNBS treatment resulted in long-term hyperalgesia and anxiety-like behavior in rats. CP rats exhibited increased FOS expression and potentiated excitatory synaptic transmission within aIC. CP rats also showed up-regulated expression of VGluT1, and increased membrane trafficking and phosphorylation of NR2B and GluR1 within aIC. Blocking excitatory synaptic transmission significantly attenuated abdomen mechanical hyperalgesia. Specifically inhibiting the excitability of insular pyramidal cells reduced both abdomen hyperalgesia and pain-related anxiety. In conclusion, our findings emphasize a key role for aIC in hyperalgesia and anxiety of painful CP, providing a novel insight into cortical modulation of painful CP and shedding light on aIC as a potential target for neuromodulation interventions in the treatment of CP.

Summary: Loss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) cause paroxysmal disorders associated with defective Ca2+ dependence of glutamatergic transmission. We find that either acute or constitutive PRRT2 deletion induces a significant decrease in the amplitude of evoked excitatory postsynaptic currents (eEPSCs) that is insensitive to extracellular Ca2+ and associated with a reduced contribution of P/Q-type Ca2+ channels to the EPSC amplitude. This synaptic phenotype parallels a decrease in somatic P/Q-type Ca2+ currents due to a decreased membrane targeting of the channel with unchanged total expression levels. Co-immunoprecipitation, pull-down assays, and proteomics reveal a specific and direct interaction of PRRT2 with P/Q-type Ca2+ channels. At presynaptic terminals lacking PRRT2, P/Q-type Ca2+ channels reduce their clustering at the active zone, with a corresponding decrease in the P/Q-dependent presynaptic Ca2+ signal. The data highlight the central role of PRRT2 in ensuring the physiological Ca2+ sensitivity of the release machinery at glutamatergic synapses.

The medial prefrontal cortex (mPFC) plays a vital role in the processing of emotional events. It has been shown that activation of the glutamatergic transmission in prelimbic subregion of the mPFC (PL-PFC) evoked anxiety-like behavior in rodents. We previously reported that local perfusion of a selective agonist to delta-opioid receptor (DOP), KNT-127, attenuated the veratrine-induced elevation of extracellular glutamate in the PL-PFC and anxiety-like behavior in mice. These results suggested the possibility that KNT-127 suppresses glutamate release from the presynaptic site in the PL-PFC. To examine this possibility directly, we performed whole-cell patch-clamp recording from principal neurons in the PL-PFC and examined the spontaneous and electrically-evoked excitatory postsynaptic currents (EPSC)s. We found that bath application of KNT-127 significantly decreased the frequency of spontaneous and miniature EPSCs. Conversely, amplitude, rise time, and decay time of spontaneous and miniature EPSCs were not affected by bath application of KNT-127. Also, KNT-127 increased paired-pulse ratios of electrically-evoked EPSCs in the PL-PFC principal neurons tested. Further, we analyzed the firing properties of pyramidal neurons in the PL-PFC and found that KNT-127 treatment significantly reduced the number of action potentials and firing threshold. These results suggested that KNT-127 suppresses glutamatergic synaptic transmission by inhibiting glutamate release from the presynaptic site and reduces neuronal excitability in the mouse PL-PFC. We propose the possibility that these suppressing effects of KNT-127 on PL-PFC activity are part of the underlying mechanisms of its anxiolytic-like effects. • KNT-127 decreases frequency of sEPSC and mEPSCs in the PL-PFC. • KNT-127 increases the paired-pulse ratio of eEPSCs in the PL-PFC. • KNT-127 suppresses action potential firing and increases rheobase in the PL-PFC. • KNT-127 inhibits glutamate release from presynapse via DOP in the PL-PFC. • KNT-127 decreases cellular excitability of principal neuron in the PL-PFC. [ABSTRACT FROM AUTHOR]

Summary: Coordinated intracellular and extracellular signaling is critical to synapse development and functional neural circuit wiring. Here, we report that unesterified docosahexaenoic acid (DHA) regulates functional synapse formation in vivo via retinoid X receptor α (Rxra) signaling. Using Rxra conditional knockout (cKO) mice and virus-mediated transient gene expression, we show that endogenous Rxra plays important roles in regulating spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. We further show that the effects of RXRA are mediated through its DNA-binding domain in a cell-autonomous and reversible manner. Moreover, unesterified DHA increases spine formation and excitatory synaptic transmission in vivo in an Rxra-dependent fashion. Rxra cKO mice generally behave normally but show deficits in behavior tasks associated with social memory. Together, these results demonstrate that unesterified DHA signals through RXRA to regulate spinogenesis and functional synapse formation, providing insight into the mechanism through which DHA promotes brain development and cognitive function.

Songbirds are useful vertebrate study models for vocal learning and memory. The robust nucleus of the arcopallium (RA) receives synaptic inputs from both the posterior and anterior pathways of the song control system in songbirds. Hence, RA plays an important role in the control of singing. RA receives dopaminergic (DArgic) inputs that increase the excitability of RA projection neurons (PNs). However, the effects of DA on excitatory synaptic transmission are yet to be deciphered. In this study, the effects of DA on the excitatory synaptic transmission of the PNs in the RA of adult male zebra finches were investigated using a whole-cell patch-clamp recording. We observed that DA decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs). The effects of DA were mimicked by the D1-like DA receptor (D1R) agonist, SKF-38393, but not the D2-like DA receptor (D2R) agonist, Quinpirole. Also, the effects of DA were blocked by D1R antagonist, SCH-23390, but not the D2R antagonist, Sulpiride. These results demonstrate that DA modulates excitatory synaptic transmission by acting on D1R in the RA of adult male zebra finches.

The post-synaptic density protein 95 (PSD-95) plays a central role in excitatory synapse development and synaptic plasticity. Phosphorylation of the N-terminus of PSD-95 at threonine 19 (T19) and serine 25 (S25) decreases PSD-95 stability at synapses; however, a molecular mechanism linking PSD-95 phosphorylation to altered synaptic stability is lacking. Here, we show that phosphorylation of T19/S25 recruits the phosphorylation-dependent peptidyl-prolyl cis–trans isomerase (Pin1) and reduces the palmitoylation of Cysteine 3 and Cysteine 5 in PSD-95. This reduction in PSD-95 palmitoylation accounts for the observed loss in the number of dendritic PSD-95 clusters, the increased AMPAR mobility, and the decreased number of functional excitatory synapses. We find the effects of Pin1 overexpression were all rescued by manipulations aimed at increasing the levels of PSD-95 palmitoylation. Therefore, Pin1 is a key signaling molecule that regulates the stability of excitatory synapses and may participate in the destabilization of PSD-95 following the induction of synaptic plasticity.

Phosphorylation-dependent peptidyl-prolyl cis-trans isomerization plays key roles in cell cycle progression, the pathogenesis of cancer, and age-related neurodegeneration. Most of our knowledge about the role of phosphorylation-dependent peptidyl-prolyl cis-trans isomerization and the enzyme catalyzing this reaction, the peptidyl-prolyl isomerase (Pin1), is largely limited to proteins not present in neurons. Only a handful of examples have shown that phosphorylation-dependent peptidyl-prolyl cis-trans isomerization, Pin1 binding, or Pin1-mediated peptidyl-prolyl cis-trans isomerization regulate proteins present at excitatory synapses. In this work, I confirm previous findings showing that Pin1 binds postsynaptic density protein-95 (PSD-95) and identify an alternative binding site in the phosphorylated N-terminus of the PSD-95. Pin1 associates via its WW domain with phosphorylated threonine (T19) and serine (S25) in the N-terminus domain of PSD-95 and this association alters the local conformation of PSD-95. Most importantly, I show that proline-directed phosphorylation of the N-terminus domain of PSD-95 alters the local conformation of this region. Therefore, proline-directed phosphorylation of the N-terminus of PSD-95, Pin1 association, and peptidyl-prolyl cis-trans isomerization may all play a role in excitatory synaptic function and synapse development.

AMPA‐type glutamate receptors (AMPARs) are key molecules of neuronal communication in our brain. The discovery of AMPAR auxiliary subunits, such as proteins of the TARP, CKAMP and CNIH families, fundamentally changed our understanding of how AMPAR function is regulated. Auxiliary subunits control almost all aspects of AMPAR function in the brain. They influence AMPAR assembly, composition, structure, trafficking, subcellular localization and gating. This influence has important implications for synapse function. In the present review, we first discuss how auxiliary subunits affect the strength of synapses by modulating number and localization of AMPARs in synapses as well as their glutamate affinity, conductance and peak open probability. Next we explain how the presence of auxiliary subunits alters temporal precision and integrative properties of synapses by influencing gating kinetics of the receptors. Auxiliary subunits of the TARP and CKAMP family modulate synaptic short‐term plasticity by increasing anchoring of AMPARs in synapses and by altering their desensitization kinetics. We then describe how auxiliary subunits of the TARP, CKAMP and CNIH families are involved in Hebbian and homeostatic plasticity, which can be explained by their influence on surface trafficking and synaptic targeting. In conclusion, the series of studies covered in this review show that auxiliary subunits play a pivotal role in controlling information processing in the brain by modulating synaptic computation. [ABSTRACT FROM AUTHOR]

Key points: Fasting can increase motivation for food and can energize reward‐seeking.Ventral tegmental area (VTA) dopamine neurons respond to motivationally relevant information and fasting can influence mesolimbic dopamine concentration.An acute overnight fast differentially alters food approach behaviours and excitatory synaptic transmission onto VTA dopamine neurons of male or female mice.While inhibitory synapses onto VTA dopamine neurons are not altered by fasting in male or female mice, male mice had strengthened excitatory synapses whereas female mice had increased endocannabinoid‐mediated short‐term plasticity at excitatory synapses.These results help us understand how fasting differentially influences excitatory synaptic transmission onto dopamine neurons and may inform different strategies for fasting‐induced food seeking by male and female mice. Dopamine neurons in the ventral tegmental area (VTA) are important for energizing goal‐directed behaviour towards food and are sensitive to changes in metabolic states. Fasting increases the incentive motivation for food and the mobilization of energy stores and has sex‐dependent effects. However, it is unknown how acute fasting alters excitatory or inhibitory synaptic transmission onto VTA dopamine neurons. An acute 16 h overnight fast induced increased food‐seeking behaviour that was more predominant in male mice. Fasting increased miniature excitatory postsynaptic current frequency and amplitude in male, but not female, mice. This effect was not due to altered release probability as there was no change in the paired pulse ratio, nor was it due to an altered postsynaptic response as there was no change in the AMPA receptor/NMDA receptor ratio or response to glutamate uncaging. However, this effect was consistent with an increase in the number of release sites. In addition, depolarization‐induced suppression of excitation, a measure of short‐term endocannabinoid‐mediated plasticity, was enhanced in female but not male fasted mice. There were no fasting‐induced changes at inhibitory synapses onto dopamine neurons of male or female mice. Taken together, these results demonstrate that fasting influences excitatory synapses differentially in male and female mice, but preserves inhibitory synapses onto dopamine neurons, indicating that the mesolimbic circuits of male and female mice respond differently to acute energy deprivation. Key points: Fasting can increase motivation for food and can energize reward‐seeking.Ventral tegmental area (VTA) dopamine neurons respond to motivationally relevant information and fasting can influence mesolimbic dopamine concentration.An acute overnight fast differentially alters food approach behaviours and excitatory synaptic transmission onto VTA dopamine neurons of male or female mice.While inhibitory synapses onto VTA dopamine neurons are not altered by fasting in male or female mice, male mice had strengthened excitatory synapses whereas female mice had increased endocannabinoid‐mediated short‐term plasticity at excitatory synapses.These results help us understand how fasting differentially influences excitatory synaptic transmission onto dopamine neurons and may inform different strategies for fasting‐induced food seeking by male and female mice. [ABSTRACT FROM AUTHOR]

In this study, the effect of extracellular pH on glutamatergic synaptic transmission was examined in mechanically dissociated rat hippocampal CA3 pyramidal neurons using a whole-cell patch-clamp technique under voltage-clamp conditions. Native synaptic boutons were isolated without using any enzymes, using a so-called “synapse bouton preparation,” and preserved for the electrical stimulation of single boutons. Both the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) were found to decrease and increase in response to modest acidic (~pH 6.5) and basic (~pH 8.5) solutions, respectively. These changes in sEPSC frequency were not affected by the addition of TTX but completely disappeared by successive addition of Cd2+. However, changes in sEPSC amplitude induced by acidic and basic extracellular solutions were not affected by the addition of neither TTX nor Cd2+. The glutamate-induced whole-cell currents were decreased and increased by acidic and basic solutions, respectively. Acidic pH also decreased the amplitude and increased the failure rate (Rf) and paired-pulse rate (PPR) of glutamatergic electrically evoked excitatory postsynaptic currents (eEPSCs), while a basic pH increased the amplitude and decreased both the Rf and PPR of eEPSCs. The kinetics of the currents were not affected by changes in pH. Acidic and basic solutions decreased and increased voltage-gated Ca2+ but not Na+ channel currents in the dentate gyrus granule cell bodies. Our results indicate that extracellular pH modulates excitatory transmission via both pre- and postsynaptic sites, with the presynaptic modulation correlated to changes in voltage-gated Ca2+ channel currents. [ABSTRACT FROM AUTHOR]

Songbirds are useful vertebrate study models for vocal learning and memory. The robust nucleus of the arcopallium (RA) receives synaptic inputs from both the posterior and anterior pathways of the song control system in songbirds. Hence, RA plays an important role in the control of singing. RA receives dopaminergic (DArgic) inputs that increase the excitability of RA projection neurons (PNs). However, the effects of DA on excitatory synaptic transmission are yet to be deciphered. In this study, the effects of DA on the excitatory synaptic transmission of the PNs in the RA of adult male zebra finches were investigated using a whole-cell patch-clamp recording. We observed that DA decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs). The effects of DA were mimicked by the D1-like DA receptor (D1R) agonist, SKF-38393, but not the D2-like DA receptor (D2R) agonist, Quinpirole. Also, the effects of DA were blocked by D1R antagonist, SCH-23390, but not the D2R antagonist, Sulpiride. These results demonstrate that DA modulates excitatory synaptic transmission by acting on D1R in the RA of adult male zebra finches. [ABSTRACT FROM AUTHOR]

Phosphorylation-dependent peptidyl-prolyl cis-trans isomerization plays key roles in cell cycle progression, the pathogenesis of cancer, and age-related neurodegeneration. Most of our knowledge about the role of phosphorylation-dependent peptidyl-prolyl cis-trans isomerization and the enzyme catalyzing this reaction, the peptidyl-prolyl isomerase (Pin1), is largely limited to proteins not present in neurons. Only a handful of examples have shown that phosphorylation-dependent peptidyl-prolyl cis-trans isomerization, Pin1 binding, or Pin1-mediated peptidyl-prolyl cis-trans isomerization regulate proteins present at excitatory synapses. In this work, I confirm previous findings showing that Pin1 binds postsynaptic density protein-95 (PSD-95) and identify an alternative binding site in the phosphorylated N-terminus of the PSD-95. Pin1 associates via its WW domain with phosphorylated threonine (T19) and serine (S25) in the N-terminus domain of PSD-95 and this association alters the local conformation of PSD-95. Most importantly, I show that proline-directed phosphorylation of the N-terminus domain of PSD-95 alters the local conformation of this region. Therefore, proline-directed phosphorylation of the N-terminus of PSD-95, Pin1 association, and peptidyl-prolyl cis-trans isomerization may all play a role in excitatory synaptic function and synapse development. [ABSTRACT FROM AUTHOR]

The post-synaptic density protein 95 (PSD-95) plays a central role in excitatory synapse development and synaptic plasticity. Phosphorylation of the N-terminus of PSD-95 at threonine 19 (T19) and serine 25 (S25) decreases PSD-95 stability at synapses; however, a molecular mechanism linking PSD-95 phosphorylation to altered synaptic stability is lacking. Here, we show that phosphorylation of T19/S25 recruits the phosphorylation-dependent peptidyl-prolyl cis–trans isomerase (Pin1) and reduces the palmitoylation of Cysteine 3 and Cysteine 5 in PSD-95. This reduction in PSD-95 palmitoylation accounts for the observed loss in the number of dendritic PSD-95 clusters, the increased AMPAR mobility, and the decreased number of functional excitatory synapses. We find the effects of Pin1 overexpression were all rescued by manipulations aimed at increasing the levels of PSD-95 palmitoylation. Therefore, Pin1 is a key signaling molecule that regulates the stability of excitatory synapses and may participate in the destabilization of PSD-95 following the induction of synaptic plasticity. [ABSTRACT FROM AUTHOR]

Abstract The tree shrew, as a primate-like animal model, has been used for studying high brain functions such as social emotion and spatial learning memory. However, little is known about the excitatory synaptic transmission in cortical brain areas of the tree shrew. In the present study, we have characterized the excitatory synaptic transmission and intrinsic properties of pyramidal neurons in the anterior cingulate cortex (ACC) of the adult tree shrew, a key cortical region for pain perception and emotion. We found that glutamate is the major excitatory transmitter for fast synaptic transmission. Excitatory synaptic responses induced by local stimulation were mediated by AMPA and kainate (KA) receptors. As compared with mice, AMPA and KA receptor mediated responses were significantly greater. Interestingly, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in tree shrews was significantly less than that of mice. Moreover, both the ratio of paired-pulse facilitation (PPF) and the time of 50% decay for fast blockade of NMDA receptor mediated EPSCs were greater in the tree shrew. Finally, tree shrew neurons showed higher initial firing frequency and neuronal excitability with a cell type-specific manner in the ACC. Our studies provide the first report of the basal synaptic transmission in the ACC of adult tree shrew.

Key points: Triheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS.Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors.GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+.GluN2B‐selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors.These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors. Triheteromeric NMDA‐type glutamate receptors that contain two GluN1 and two different GluN2 subunits contribute to excitatory neurotransmission in the adult CNS. In the present study, we report properties of the triheteromeric GluN1/2B/2D NMDA receptor subtype that is expressed in distinct neuronal populations throughout the CNS. We show that neither GluN2B, nor GluN2D dominate the functional properties of GluN1/2B/2D receptors because agonist potencies, open probability and the glutamate deactivation time course of GluN1/2B/2D receptors are intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. Furthermore, channel blockade of GluN1/2B/2D by extracellular Mg2+ is intermediate compared to GluN1/2B and GluN1/2D, although GluN1/2B/2D is more sensitive to blockade by ketamine and memantine compared to GluN1/2B in the presence of physiological Mg2+. Subunit‐selective allosteric modulators have distinct activity at GluN1/2B/2D receptors, including GluN2B‐selective antagonists, ifenprodil, EVT‐101 and CP‐101‐606, which inhibit with similar potencies but with different efficacies at GluN1/2B/2D (∼65% inhibition) compared to GluN1/2B (∼95% inhibition). Furthermore, the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors. We show that these key features of allosteric modulation of recombinant GluN1/2B/2D receptors are also observed for NMDA receptors in hippocampal interneurons but not CA1 pyramidal cells, which is consistent with the expression of GluN1/2B/2D receptors in interneurons and GluN1/2A/2B receptors in pyramidal cells. Altogether, we uncover previously unknown functional and pharmacological properties of triheteromeric GluN1/2B/2D receptors that can facilitate advances in our understanding of their physiological roles in neural circuit function and therapeutic drug actions. Key points: Triheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the CNS.Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors.GluN1/2B/2D receptors are more sensitive to channel blockade by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg2+.GluN2B‐selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B‐selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D but not GluN1/2A/2B receptors.These insights into the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors. [ABSTRACT FROM AUTHOR]

Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho GTPase family which plays important roles in dendritic spine morphology and plasticity, is a key regulator of cytoskeletal reorganization in dendrites and spines. Here, we investigated whether and how Rac1 modulates synaptic transmission in mouse retinal ganglion cells (RGCs) using selective conditional knockout of Rac1 (Rac1-cKO). Rac1-cKO significantly reduced the frequency of AMPA receptor-mediated miniature excitatory postsynaptic currents, while glycine/GABAA receptor-mediated miniature inhibitory postsynaptic currents were not affected. Although the total GluA1 protein level was increased in Rac1-cKO mice, its expression in the membrane component was unchanged. Rac1-cKO did not affect spine-like branch density in single dendrites, but significantly reduced the dendritic complexity, which resulted in a decrease in the total number of dendritic spine-like branches. These results suggest that Rac1 selectively affects excitatory synaptic transmission in RGCs by modulating dendritic complexity. [ABSTRACT FROM AUTHOR]

• The reduction of Ca2+ influx is a relevant neuroprotective strategy. • Extracellular acidosis reduces the Ca2+ permeability of human NMDA receptors. • Extracellular acidosis reduces the single channel conductance of NMDA receptors. • pH differentially modulates Na+ and Ca2+ fluxes through NMDA receptors in neurons. • Neuronal Ca2+ overload can be reduced lowering the NMDA receptor Ca2+ permeability. NMDA receptors (NMDARs) are glutamate-gated ion channels involved in excitatory synaptic transmission and in others physiological processes such as synaptic plasticity and development. The overload of Ca2+ ions through NMDARs, caused by an excessive activation of receptors, leads to excitotoxic neuronal cell death. For this reason, the reduction of Ca2+ flux through NMDARs has been a central focus in finding therapeutic strategies to prevent neuronal cell damage. Extracellular H+ are allosteric modulators of NMDARs. Starting from previous studies showing that extracellular mild acidosis reduces NMDA-evoked whole cell currents, we analyzed the effects of this condition on the NMDARs Ca2+ permeability, measured as "fractional calcium current" (P f , i.e. the percentage of the total current carried by Ca2+ ions), of human NMDARs NR1/NR2A and NR1/NR2B transiently transfected in HeLa cells. Extracellular mild acidosis significantly reduces P f of both human NR1/NR2A and NR1/NR2B NMDARs, also decreasing single channel conductance in outside out patches for NR1/NR2A receptor. Reduction of Ca2+ flux through NMDARs was also confirmed in cortical neurons in culture. A comparative analysis of both NMDA evoked Ca2+ transients and whole cell currents showed that extracellular H+ differentially modulate the permeation of Na+ and Ca2+ through NMDARs. Our data highlight the synergy of two distinct neuroprotective mechanisms during acidosis: Ca2+ entry through NMDARs is lowered due to the modulation of both open probability and Ca2+ permeability. Furthermore, this study provides the proof of concept that it is possible to reduce Ca2+ overload in neurons modulating the NMDAR Ca2+ permeability. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that the endocrine hormone leptin regulates hippocampal synaptic function in addition to its established role as a hypothalamic satiety signal. Indeed, numerous studies show that leptin facilitates the cellular events that underlie hippocampal learning and memory including activity-dependent synaptic plasticity and glutamate receptor trafficking, indicating that leptin may be a potential cognitive enhancer. Although there has been extensive investigation into the modulatory role of leptin at hippocampal Schaffer collateral (SC)-CA1 synapses, recent evidence indicates that leptin also potently regulates excitatory synaptic transmission at the anatomically distinct temporoammonic (TA) input to hippocampal CA1 neurons. The cellular mechanisms underlying activity-dependent synaptic plasticity at TA-CA1 synapses differ from those at SC-CA1 synapses and the TA input is implicated in spatial and episodic memory formation. Furthermore, the TA input is an early target for neurodegeneration in Alzheimer's disease (AD) and aberrant leptin function is linked to AD. Here, we review the evidence that leptin regulates hippocampal synaptic function at both SC- and TA-CA1 synapses and discuss the consequences for neurodegenerative disorders like AD. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that diet and body weight are important factors associated with Alzheimer's disease (AD), with a significant increase in AD risk linked to mid-life obesity, and weight loss frequently occurring in the early stages of AD. This has fuelled interest in the hormone leptin, as it is an important hypothalamic regulator of food intake and body weight, but leptin also markedly influences the functioning of the hippocampus; a key brain region that degenerates in AD. Increasing evidence indicates that leptin has cognitive enhancing properties as it facilitates the cellular events that underlie hippocampal-dependent learning and memory. However, significant reductions in leptin's capacity to regulate hippocampal synaptic function occurs with age and dysfunctions in the leptin system are associated with an increased risk of AD. Moreover, leptin is a potential novel target in AD as leptin treatment has beneficial effects in various models of AD. Here we summarise recent advances in leptin neurobiology with particular focus on regulation of hippocampal synaptic function by leptin and the implications of this for neurodegenerative disorders like AD. This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’ [ABSTRACT FROM AUTHOR]

It has been generally accepted that pain can cause imbalance between excitation and inhibition (homeostasis) at the synaptic level. However, it remains poorly understood how this imbalance (allostasis) develops in the CNS under different pain conditions. Here, we analyzed the changes in both excitatory and inhibitory synaptic transmission and modulation of the dentate gyrus (DG) under two pain conditions with different etiology and duration. First, it was revealed that the functions of the input-output (I/O) curves for evoked excitatory postsynaptic currents (eEPSCs) following the perforant path (PP) stimulation were gained under both acute inflammatory and chronic neuropathic pain conditions relative to the controls. However, the functions of I/O curves for the PP-evoked inhibitory postsynaptic currents (eIPSCs) differed between the two conditions, namely it was greatly gained under inflammatory condition, but was reduced under neuropathic condition in reverse. Second, both the frequency and amplitude of miniature IPSCs (mIPSCs) were increased under inflammatory condition, however a decrease in frequency of mIPSCs was observed under neuropathic condition. Finally, the spike discharge of the DG granule cells in response to current injection was significantly increased by neuropathic pain condition, however, no different change was found between inflammatory pain condition and the control. These results provide another line of evidence showing homeostatic and allostatic modulation of excitatory synaptic transmission by inhibitory controls under different pathological pain conditions, hence implicating use of different therapeutic approaches to maintain the homeostasis between excitation and inhibition while treating different conditions of pathological pain.