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Postoperative delirium (POD), a syndrome of confusion and inattention, frequently occurs after anesthesia and surgery. The prefrontal cortex (PFC) plays key roles in executive functions and cognitive controls. However, the neuropathogenesis of POD in the PFC remains largely unknown. We investigated whether anesthesia and surgery induced neurofunctional changes in the mouse PFC. After laparotomy was performed under isoflurane anesthesia, PFC neuronal activities were compared at the synaptic level using whole-cell patch-clamp recordings. A battery of behavioral tests measuring natural and learned behaviors, and effects of intraoperative dexmedetomidine were also examined. In the anesthesia/surgery group showing changes in natural and learned behaviors, the frequency of excitatory synaptic responses in PFC pyramidal neurons was decreased after the surgery without any changes in the response kinetics. On the other hand, neuronal intrinsic properties and inhibitory synaptic responses were not changed. In the anesthesia/surgery group administered intraoperative dexmedetomidine, the excitatory synaptic transmission and the behaviors were not altered. These results suggest that anesthesia and surgery induce a functional reduction selectively in the PFC excitatory synaptic transmission, and intraoperative dexmedetomidine inhibits the plastic change in the PFC excitatory synaptic input. more...

Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactivity and seizures. While many forms of homeostasis have been described, whether and how the magnitude of homeostatic plasticity is constrained remains unknown. Here, we uncover negative regulation of cortical network homeostasis by the PARbZIP family of transcription factors. In cortical slice cultures made from knockout mice lacking all three of these factors, the network response to prolonged activity withdrawal measured with calcium imaging is much stronger, while baseline activity is unchanged. Whole-cell recordings reveal an exaggerated increase in the frequency of miniature excitatory synaptic currents reflecting enhanced upregulation of recurrent excitatory synaptic transmission. Genetic analyses reveal that two of the factors, Hlf and Tef, are critical for constraining plasticity and for preventing life-threatening seizures. These data indicate that transcriptional activation is not only required for many forms of homeostatic plasticity but is also involved in restraint of the response to activity deprivation. more...

Neuropeptides influence animal behaviors through complex molecular and cellular mechanisms, many of which are difficult to predict solely from synaptic connectivity. Here, we uncovered two separate downstream targets that are differentially modulated by the neuropeptide tachykinin, which promotes Drosophila aggression. Tachykinin from a single sexually dimorphic group of neurons recruits two separate downstream groups of neurons. One downstream group, synaptically connected to the tachykinergic neurons, expresses the receptor TkR86C and is necessary for aggression. Tachykinin supports the strength of cholinergic excitatory synaptic transmission between the tachykinergic and TkR86C downstream neurons. The other downstream group expresses the TkR99D receptor and is recruited primarily when tachykinin is over-expressed in the source neurons. This circuit reconfiguration correlates with the quantitative and qualitative enhancement of aggression observed when tachykinin is present in excess. Our data highlight how the amount of neuropeptide released from a small number of neurons can reshape the activity patterns of multiple downstream neural populations. more...

BACKGROUND Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). We hypothesized that the nucleus tractus solitarius (NTS), a primary central site that integrates pancreatic afferents apart from the thoracic spinal dorsal horn, plays a key role in the pathogenesis of visceral hypersensitivity in a rat model of CP. AIM To investigate the role of the NTS in the visceral hypersensitivity induced by chronic pancreatitis. METHODS CP was induced by the intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Pancreatic hyperalgesia was assessed by referred somatic pain via von Frey filament assay. Neural activation of the NTS was indicated by immunohistochemical staining for Fos. Basic synaptic transmission within the NTS was assessed by electrophysiological recordings. Expression of vesicular glutamate transporters (VGluTs), N-methyl-D-aspartate receptor subtype 2B (NR2B), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1 (GluR1) was analyzed by immunoblotting. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. The regulatory role of the NTS in visceral hypersensitivity was detected via pharmacological approach and chemogenetics in CP rats. RESULTS TNBS treatment significantly increased the number of Fos-expressing neurons within the caudal NTS. The excitatory synaptic transmission was substantially potentiated within the caudal NTS in CP rats (frequency: 5.87 ± 1.12 Hz in CP rats vs 2.55 ± 0.44 Hz in sham rats, P < 0.01; amplitude: 19.60 ± 1.39 pA in CP rats vs 14.71 ± 1.07 pA in sham rats; P < 0.01). CP rats showed upregulated expression of VGluT2, and increased phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission via the AMPAR antagonist CNQX and the NMDAR antagonist AP-5 microinjection reversed visceral hypersensitivity in CP rats (abdominal withdraw threshold: 7.00 ± 1.02 g in CNQX group, 8.00 ± 0.81 g in AP-5 group and 1.10 ± 0.27 g in saline group, P < 0.001). Inhibiting the excitability of NTS neurons via chemogenetics also significantly attenuated pancreatic hyperalgesia (abdominal withdraw threshold: 13.67 ± 2.55 g in Gi group, 2.00 ± 1.37 g in Gq group, and 2.36 ± 0.67 g in mCherry group, P < 0.01). CONCLUSION Our findings suggest that enhanced excitatory transmission within the caudal NTS contributes to pancreatic pain and emphasize the NTS as a pivotal hub for the processing of pancreatic afferents, which provide novel insights into the central sensitization of painful CP. more...

The present study evaluated the ability of progesterone to alleviate the synaptic transmission disturbed by hypoxia in the nucleus tractus solitarius (NTS). Hypoxia with N2 inhibited spontaneous and tractus solitarius-evoked excitatory postsynaptic currents (sEPSCs and eEPSCs) in NTS neurons of the rat brainstem slice. An additional application of progesterone counteracted the hypoxia-induced inhibition of sEPSCs and eEPSCs without affecting the baseline currents. This effect of progesterone occurred rapidly and reversibly. Progesterone had neither effect on sEPSCs nor eEPSCs in normoxia. These results suggest that progesterone restores hypoxia-induced disturbance of the NTS glutamatergic transmission, presumably by a presynaptic, non-genomic mechanism. Keywords: Progesterone, Hypoxia, Nucleus tractus solitarius more...

Migraine is a common but poorly understood sensory circuit disorder. Mouse models of familial hemiplegic migraine (FHM, a rare monogenic form of migraine with aura) show increased susceptibility to cortical spreading depression (CSD, the phenomenon that underlies migraine aura and can activate migraine headache mechanisms), allowing an opportunity to investigate the mechanisms of CSD and migraine onset. In FHM type 2 (FHM2) knock-in mice with reduced expression of astrocytic Na+, K+-ATPases, the reduced rate of glutamate uptake into astrocytes can account for the facilitation of CSD initiation. Here, we investigated the underlying mechanisms and show that the reduced rate of glutamate clearance in FHM2 mice results in increased amplitude and slowing of rise time and decay of the NMDA receptor (NMDAR) excitatory postsynaptic current (EPSC) elicited in layer 2/3 pyramidal cells by stimulation of neuronal afferents in somatosensory cortex slices. The relative increase in NMDAR activation in FHM2 mice is activity-dependent, being larger after high-frequency compared to low-frequency afferent activity. Inhibition of GluN1-N2B NMDARs, which hardly affected the NMDAR EPSC in wild-type mice, rescued the increased and prolonged activation of NMDARs as well as the facilitation of CSD induction and propagation in FHM2 mice. Our data suggest that the enhanced susceptibility to CSD in FHM2 is mainly due to specific activation of extrasynaptic GluN1-N2B NMDARs and point to these receptors as possible therapeutic targets for prevention of CSD and migraine. more...

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., Graphical abstract, Highlights • PRRT2 deficiency reduces the contribution of P/Q-type Ca2+ channels to the EPSC • PRRT2 deficiency decreases P/Q-type currents and membrane targeting of the channels • PRRT2 directly interacts with P/Q-type Ca2+ channels • PRRT2 deficiency reduces P/Q-channel clustering and Ca2+ signals in nerve terminals, PRRT2 deficiency causes paroxysmal disorders associated with defective Ca2+ dependence of glutamatergic transmission. Ferrante et al. now find that, in the absence of PRRT2, the membrane targeting of P/Q-type Ca2+ channels is reduced, and the channels fail to concentrate at the nanodomain where the machinery for synchronous release is assembled. more...

Background A polygenic risk score (PRS) derived from genome-wide association studies of posttraumatic stress disorder (PTSD) may inform risk for this disorder. To date, however, no known study has examined whether social environmental factors such as attachment style may moderate the relation between PRS and PTSD. Methods We evaluated main and interactive effects of PRS and attachment style on PTSD symptoms in a nationally representative sample of trauma-exposed European-American U.S. military veterans (N = 2030). PRS was derived from a genome-wide association study of PTSD re-experiencing symptoms (N = 146,660) in the Million Veteran Program cohort. Using one-sample Mendelian randomization with data from the UK Biobank (N = 115,099), we evaluated the effects of re-experiencing PRS and attachment style on PTSD symptoms. Results Higher re-experiencing PRS and secure attachment style were independently associated with PTSD symptoms. A significant PRS-by-attachment style interaction was also observed (β = −.11, p = .006), with a positive association between re-experiencing PRS and PTSD symptoms observed only among veterans with an insecure attachment style. One-sample Mendelian randomization analyses suggested that the association between PTSD symptoms and attachment style is bidirectional. PRS enrichment analyses revealed a significant interaction between attachment style and a variant mapping to the IGSF11 gene (rs151177743, p = 2.1 × 10−7), which is implicated in regulating excitatory synaptic transmission and plasticity. Conclusions Attachment style may moderate polygenic risk for PTSD symptoms, and a novel locus implicated in synaptic transmission and plasticity may serve as a possible biological mediator of this association. These findings may help inform interpersonally oriented treatments for PTSD for individuals with high polygenic risk for this disorder. more...

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. more...

N-methyl-D-aspartate receptors (NMDARs) are a family of ionotropic glutamate receptors mainly known to mediate excitatory synaptic transmission and plasticity. Interestingly, low-dose NMDAR antagonists lead to increased, instead of decreased, functional connectivity; and they could cause schizophrenia- and/or antidepressant-like behavior in both humans and rodents. In addition, human genetic evidences indicate that NMDAR loss of function mutations underlie certain forms of epilepsy, a disease featured with abnormal brain hyperactivity. Together, they all suggest that under certain conditions, NMDAR activation actually lead to inhibition, but not excitation, of the global neuronal network. Apparently, these phenomena are rather counterintuitive to the receptor's basic role in mediating excitatory synaptic transmission. How could it happen? Recently, this has become a crucial question in order to fully understand the complexity of NMDAR function, particularly in disease. Over the past decades, different theories have been proposed to address this question. These include theories of “NMDARs on inhibitory neurons are more sensitive to antagonism”, or “basal NMDAR activity actually inhibits excitatory synapse”, etc. Our review summarizes these efforts, and also provides an introduction of NMDARs, inhibitory neurons, and their relationships with the related diseases. Advances in the development of novel NMDAR pharmacological tools, particularly positive allosteric modulators, are also included to provide insights into potential intervention strategies. more...

Naturally occurring hormone cycles in adult female humans and rodents create a dynamic neuroendocrine environment. These cycles include the menstrual cycle in humans and its counterpart in rodents, the estrous cycle. These hormone fluctuations induce sex differences in the phenotypes of many behaviors, including those related to motivation, and associated disorders such as depression and addiction. This suggests that the neural substrate instrumental for these behaviors, including the nucleus accumbens core (AcbC), likewise differs between estrous cycle phases. It is unknown whether the electrophysiological properties of AcbC output neurons, medium spiny neurons (MSNs), change between estrous cycle phases. This is a critical knowledge gap given that MSN electrophysiological properties are instrumental for determining AcbC output to efferent targets. Here we test whether the intrinsic electrophysiological properties of adult rat AcbC MSNs differ across female estrous cycle phases and from males. We recorded MSNs with whole cell patch-clamp technique in two experiments, the first using gonad-intact adult males and females in differing phases of the estrous cycle and the second using gonadectomized males and females in which the estrous cycle was eliminated. MSN intrinsic electrophysiological and excitatory synaptic input properties robustly changed between female estrous cycle phases and males. Sex differences in MSN electrophysiology disappeared when the estrous cycle was eliminated. These novel findings indicate that AcbC MSN electrophysiological properties change across the estrous cycle, providing a new framework for understanding how biological sex and hormone cyclicity regulate motivated behaviors and other AcbC functions and disorders. NEW & NOTEWORTHY This research is the first demonstration that medium spiny neuron electrophysiological properties change across adult female hormone cycle phases in any striatal region. This influence of estrous cycle engenders sex differences in electrophysiological properties that are eliminated by gonadectomy. Broadly, these findings indicate that adult female hormone cycles are an important factor for neurophysiology. more...

Periodic up and down transitions of membrane potentials are considered to be a significant spontaneous activity. These kinds of oscillations always accompany with some spontaneous firing in up state. Our previous theoretical studies mainly looked at the subthreshold up and down transitions and characteristics of up and down dynamics. In this paper, we focus on suprathreshold spontaneous firing of up and down transitions based on improved network model and its stimulations. The simulated results indicate that fast sodium current is critical to the generation of spontaneous neural firing. While persistent sodium current plays a part in spontaneous fluctuation. Both intrinsic fast and persistent sodium dynamics influence spontaneous firing rate and synchronous activity in up and down behavior. Meanwhile, blocking excitatory synaptic transmission decreases neural firing and reveals spontaneous firing. These simulated results are basically in accordance with experimental results. Through the observation and analysis of the findings, we prove the validity of the model so we can further adopt this model to study other properties and characteristics of the network, laying the foundation for further work on cortex activity. more...

The astrocyte, a major glial cell type, is involved in formation and maturation of synapses, and thus contributes to sustainable synaptic transmission between neurons. Given that the animals in the higher phylogenetic tree have brains with 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 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 evoked excitatory postsynaptic current (EPSC) than that of neurons with a lower astrocytic density. The size of readily releasable pool of synaptic vesicles per neuron was significantly higher. The frequency of spontaneous synaptic transmission (miniature EPSC) was higher, but the amplitude was unchanged. The number of morphologically identified glutamatergic synapses was unchanged, but the number 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 number of functional synapses through presynaptic un-silencing. more...

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. more...

The lateral (LA) and basolateral (BL) nuclei of the amygdala regulate emotional behaviors. Despite their dissimilar extrinsic connectivity, they are often combined, perhaps because their cellular composition is similar to that of the cerebral cortex, including excitatory principal cells reciprocally connected with fast-spiking interneurons (FSIs). In the cortex, this microcircuitry produces gamma oscillations that support information processing and behavior. We tested whether this was similarly the case in the rat (males) LA and BL using extracellular recordings, biophysical modeling, and behavioral conditioning. During periods of environmental assessment, both nuclei exhibited gamma oscillations that stopped upon initiation of active behaviors. Yet, BL exhibited more robust spontaneous gamma oscillations than LA. The greater propensity of BL to generate gamma resulted from several microcircuit differences, especially the proportion of FSIs and their interconnections with principal cells. Furthermore, gamma in BL but not LA regulated the efficacy of excitatory synaptic transmission between connected neurons. Together, these results suggest fundamental differences in how LA and BL operate. Most likely, gamma in LA is externally driven, whereas in BL it can also arise spontaneously to support ruminative processing and the evaluation of complex situations. SIGNIFICANCE STATEMENT The basolateral amygdala (BLA) participates in the production and regulation of emotional behaviors. It is thought to perform this using feedforward circuits that enhance stimuli that gain emotional significance and directs them to valence-appropriate downstream effectors. This perspective overlooks the fact that its microcircuitry is recurrent and potentially capable of generating oscillations in the gamma band (50–80 Hz), which synchronize spiking activity and modulate communication between neurons. This study found that BLA gamma supports both of these processes, is associated with periods of action selection and environmental assessment regardless of valence, and differs between BLA subnuclei in a manner consistent with their heretofore unknown microcircuit differences. Thus, it provides new mechanisms for BLA to support emotional behaviors. more...

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. more...

Background and aim: Developing fast-acting antidepressants attracts considerable attention. Anemoside A3, a natural triterpenoid glycoside isolated from Pulsatillae Radix, has been reported to produce antidepressant-like action in the forced swim test. We herein explore the fast-onset antidepressant-like potentials and antidepressant mechanisms of anemoside A3. Methods: The forced swim test and tail suspension test were used to determine the acute antidepressant-like action of anemoside A3. This action of anemoside A3 was confirmed in chronic mild stress and chronic social defeat stress models. In vitro extracellular field potential recordings were conducted to investigate the impact of anemoside A3 on chronic stress-induced alterations at temporoammonic-CA1 synapses. Western blot, whole-cell patch-clamp recordings, and microinjections of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonists into the stratum lacunosum-moleculare were performed to unravel the contribution of stratum lacunosum-moleculare α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors to anemoside A3’s antidepressant-like activity. In vivo microdialysis and pharmacological depletion of serotonin were implemented to examine the role of the serotonin system in the antidepressant-like effect of anemoside A3. Results: Anemoside A3 administered intraperitoneally displayed acute antidepressant-like effects in the mouse forced swim test and tail suspension test and anemoside A3 treatment (intraperitoneally) for five days was sufficient to reverse depression-related behaviors of mice subjected to chronic stress. Accordingly, chronic social defeat stress-induced weakening of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-mediated neurotransmission in the temporoammonic-CA1 pathway and downregulation of synaptic GluA2-lacking α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor expression in the stratum lacunosum-moleculare could both be normalized by five days of anemoside A3 treatment (intraperitoneally). Moreover, intra-stratum lacunosum-moleculare infusion of GluA2-lacking α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist abolished anemoside A3’s antidepressant-like effect. Lastly, serotonin system was not implicated in anemoside A3’s antidepressant-like effect. Conclusions: Our results suggest that anemoside A3 induces a rapid antidepressant-like response by a stratum lacunosum-moleculare GluA2-lacking α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-dependent mechanism. In view of this, anemoside A3 represents a promising agent for depression treatment. more...

In an environment with easy access to highly palatable and energy-dense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons. more...

Fil: Gonzalez, Betina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Farmacologicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Instituto de Investigaciones Farmacologicas; Argentina more...

Excitatory amino acid transporters (EAATs) are membrane proteins that control excitatory synaptic transmission in the brain ([Bergles et al., 1999][1]; [Danbolt, 2001][2]; [Robinson and Jackson, 2016][3]). As classical secondary active transporters, which use the energy stored within ion gradients more...

Summary Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of Autism Spectrum Disorder (ASD). How SHANK3 insufficiency affects specific neural circuits and this is related to specific ASD symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the Ventral Tegmental Area (VTA) of mice. We identified dopamine (DA) and GABA cell-type specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors (mGluR1) during the first postnatal week restored DA neuron excitatory synapse transmission and rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired VTA function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy. more...

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. more...

Radiate and planar neurons are the two major types of multipolar neurons in the ventral cochlear nucleus (VCN). Both cell types receive monosynaptic excitatory synaptic inputs from the auditory nerve, but have different responses to sound and project to different target regions and cells. Although the intrinsic physiology and synaptic inputs to planar neurons have been previously characterized, the radiate neurons are less common and have not been as well studied. We studied both types of multipolar neurons and characterized their properties including intrinsic excitability, synaptic dynamics of their auditory nerve inputs, as well as their neural firing properties to auditory nerve stimulation. Radiate neurons had a faster member time constant and higher threshold current to fire spikes than planar neurons, but the maximal firing rate is the same for both cell types upon large current injections. Compared to planar neurons, radiate neurons showed spontaneous postsynaptic currents with smaller size, and slower but variable kinetics. Auditory nerve stimulation progressively recruited synaptic inputs that were smaller and slower in radiate neurons, over a broader range of stimulus strength. Synaptic inputs to radiate neurons showed less depression than planar neurons during low rates of repetitive activity, but the synaptic depression at higher rates was similar between two cell types. However, due to the slow kinetics of the synaptic inputs, synaptic transmission in radiate neurons showed prominent temporal summation that contributed to greater synaptic depolarization and a higher firing rate for repetitive auditory nerve stimulation at high rates. Taken together, these results show that radiate multipolar neurons integrate a large number of weak synaptic inputs over a broad dynamic range, and have intrinsic and synaptic properties that are distinct from planar multipolar neurons. These properties enable radiate neurons to generate powerful inhibitory inputs to target neurons during high levels of afferent activity. Such robust inhibition is expected to dynamically modulate the excitability of many cell types in the cochlear nuclear complex. more...

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. more...

The NMDA receptor mediates a slow component of excitatory synaptic transmission, and NMDA receptor dysfunction has been implicated in numerous neurological disorders. Thus, interest in developing modulators that are capable of regulating the channel continues to be strong. Recent research has led to the discovery of a number of compounds that hold therapeutic and clinical value. Deeper insight into the NMDA intersubunit interactions and structural motifs gleaned from the recently solved crystal structures of the NMDA receptor should facilitate a deeper understanding of how these compounds modulate the receptor.This article discusses the known pharmacology of NMDA receptors. A discussion of the patent literature since 2012 is also included, with an emphasis on those that claimed new chemical entities as regulators of the NMDA receptor.The number of patents involving novel NMDA receptor modulators suggests a renewed interest in the NMDA receptor as a therapeutic target. Subunit-selective modulators continue to show promise, and the development of new subunit-selective NMDA receptor modulators appears poised for continued growth. Although a modest number of channel blocker patents were published, successful clinical outcomes involving ketamine have led to a resurgent interest in low-affinity channel blockers as therapeutics. more...

The N-methyl-d-aspartate (NMDA) receptor, fundamental for excitatory synaptic transmission, is a tetrameric assembly of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits, of which there are four subtypes (referred to as GluN2A–GluN2D). The GluN2 subunit endows the receptor with unique pharmacological properties and shows distinct developmental and regional expression profiles, which have led to interest in GluN2-selective modulators for the receptor. One recently described compound, (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (referred to as CIQ), selectively potentiates the response of GluN2C- and GluN2D-containing NMDA receptors to agonist activation. This tetrahydroisoquinoline compound has no agonist activity on its own, and is without effect on GluN2A- and GluN2B-containing NMDA receptors. CIQ was the first positive allosteric modulator for the GluN2C and GluN2D subunits reported in the literature, and since its discovery, multiple investigations have provided insight into its mechanism, site of action, pharmacokinetic properties, and off-target activity. CIQ has also been utilized as a tool compound in animal models of fear learning, schizophrenia, and Parkinson’s disease. The compound is being used to elucidate the role of NMDA receptors in these diseases states and to demonstrate the potential therapeutic benefits of a NMDA receptor positive allosteric modulator. more...

Although intrathecally administrated galanin modulates nociceptive transmission in a biphasic manner, this has not been fully examined previously. In the present study, the action of galanin on synaptic transmission in the substantia gelatinosa (SG) neurons of adult rat spinal cord slices was examined, using the whole cell patch-clamp technique. Galanin concentration-dependently increased the frequency of spontaneous excitatory postsynaptic current (EPSC; EC50 = 2.0 nM) without changing the amplitude, indicating a presynaptic effect. This effect was reduced in a Ca2+-free, or voltage-gated Ca2+ channel blocker La3+-containing Krebs solution and was produced by a galanin type-2/3 receptor (GalR2/R3) agonist, galanin 2–11, but not by a galanin type-1 receptor (GalR1) agonist, M617. Galanin also concentration-dependently produced an outward current at −70 mV (EC50 = 44 nM), although this appeared to be contaminated by a small inward current. This outward current was mimicked by M617, but not by galanin 2–11. Moreover, galanin reduced monosynaptic Aδ-fiber- and C-fiber-evoked EPSC amplitude; the former reduction was larger than the latter. A similar action was produced by galanin 2–11, but not by M617. Spontaneous and focally evoked inhibitory (GABAergic and glycinergic) transmission was unaffected by galanin. These findings indicate that galanin at lower concentrations enhances the spontaneous release of l-glutamate from nerve terminals by Ca2+ entry from the external solution following GalR2/R3 activation, whereas galanin at higher concentrations also produces a membrane hyperpolarization by activating GalR1. Moreover, galanin reduces l-glutamate release onto SG neurons from primary afferent fibers by activating GalR2/R3. These effects could partially contribute to the behavioral effect of galanin. more...

Precise control of synaptic strength is critical for maintaining accurate network activity and normal brain functions. Several major brain diseases are related to synaptic alterations in the adult brain. Detailed descriptions of the normal physiological properties of adult synapses are scarce, mainly because of the difficulties in performing whole cell patch-clamp recording in brain slices from adult animals. Here we present the portrait of excitatory synapses and intrinsic properties of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a central structure of the mesocorticolimbic system, from youth (P14) to adulthood (P120). We found that intrinsic neuronal excitability decreased over development, mainly due to an enhancement of potassium conductance and the consequent reduction in membrane resistance. The ratio between paired-pulse synaptic responses was similar in juvenile, adolescent, and adult MSNs, suggesting that the probability of neurotransmitter release was unaltered. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)–mediated excitatory postsynaptic currents (EPSCs) decayed more slowly in adult MSN. In contrast, the kinetic properties and the subunit composition of N-methyl-d-aspartate receptor (NMDAR)–mediated EPSC in the NAc were conserved from youth to adulthood. Changes in synaptic strength were estimated from the ratio of AMPAR to NMDAR evoked and spontaneous EPSCs (AMPAR/NMDAR ratio). Although both AMPAR and NMDAR EPSCs decreased over development, there was an increase of the AMPAR/NMDAR ratio that was linked to changes in NMDAR EPSC. Furthermore, distribution of the AMPAR/NMDAR ratio was more heterogeneous in MSNs from adults, suggesting that synaptic strength is continuously refined during life. more...

Phospholipase A2(PLA2) activation enhances glutamatergic excitatory synaptic transmission in substantia gelatinosa (SG) neurons, which play a pivotal role in regulating nociceptive transmission in the spinal cord. By using melittin as a tool to activate PLA2, we examined the effect of PLA2activation on spontaneous inhibitory postsynaptic currents (sIPSCs) recorded at 0 mV in SG neurons of adult rat spinal cord slices by use of the whole cell patch-clamp technique. Melittin enhanced the frequency and amplitude of GABAergic and glycinergic sIPSCs. The enhancement of GABAergic but not glycinergic transmission was largely depressed by Na+channel blocker tetrodotoxin or glutamate-receptor antagonists (6-cyano-7-nitroquinoxaline-2,3-dione and/or dl-2-amino-5-phosphonovaleric acid) and also in a Ca2+-free Krebs solution. The effects of melittin on glycinergic sIPSC frequency and amplitude were dose-dependent with an effective concentration of ∼0.7 μM for half-maximal effect and were depressed by PLA2inhibitor 4-bromophenacyl bromide or aristolochic acid. The melittin-induced enhancement of glycinergic transmission was depressed by lipoxygenase inhibitor nordihydroguaiaretic acid but not cyclooxygenase inhibitor indomethacin. These results indicate that the activation of PLA2in the SG enhances GABAergic and glycinergic inhibitory transmission in SG neurons. The former action is mediated by glutamate-receptor activation and neuronal activity increase, possibly the facilitatory effect of PLA2activation on excitatory transmission, whereas the latter action is due to PLA2and subsequent lipoxygenase activation and is independent of extracellular Ca2+. It is suggested that PLA2activation in the SG could enhance not only excitatory but also inhibitory transmission, resulting in the modulation of nociception. more...

Four out of five people with spinal cord injury (SCI) report chronic pain. In general this chronic pain is refractory to conventional treatments. Exercise programs designed to alleviate shoulder pain, a particular subtype of nociceptive pain after SCI, have the strongest evidence for effectiveness. There is weak evidence that long term aerobic exercise can reduce chronic pain intensity in persons with SCI. The two purported mechanisms related to the amelioration of pain by exercise are enhanced descending inhibitory activity and reduced excitatory synaptic transmission, however experimental support for these mechanisms is meager. Finally there seems to be an association between exercise, pain, and mood states which may be related to common mechanisms and requires further study. more...

Information processing in neuronal networks is determined by the use-dependent dynamics of synaptic transmission. Here we characterize the dynamic properties of excitatory synaptic transmission in two major intracortical pathways that target the output neurons of the neocortex, by recording unitary EPSPs from layer 5 pyramidal neurons evoked in response to action potential trains of increasing complexity in presynaptic layer 2/3 or layer 5 pyramidal neurons. We find that layer 2/3 to layer 5 synaptic transmission is dominated by frequency-dependent depression when generated at fixed frequencies of > 10 Hz. Synaptic depression evolved on a spike-by-spike basis in response to action potential trains that possessed a broad range of interspike intervals, but a low mean frequency (10 Hz). Layer 2/3 to layer 2/3 and layer 2/3 to layer 5 synapses were incapable of sustained release during prolonged, complex trains of presynaptic action potential firing (mean frequency, 48 Hz). By contrast, layer 5 to layer 5 synapses operated effectively across a wide range of frequencies, exhibiting increased efficacy at frequencies > 10 Hz. Furthermore, layer 5 to layer 5 synapses sustained release throughout the duration of prolonged, complex spike trains. The use-dependent properties of synaptic transmission could be modulated by pharmacologically changing the probability of release and by induction of long-term depression. The dynamic properties of intracortical excitatory synapses are therefore pathway-specific. We suggest that the synaptic output of layer 5 pyramidal neurons is ideally suited to control the neocortical network across a wide range of frequencies and for sustained periods of time, a behaviour that helps to explain the pivotal role played by layer 5 neurons in the genesis of periods of network ‘up’ states and epileptiform activity in the neocortex. more...

Neuropeptide Y (NPY) is a potent modulator of excitatory synaptic transmission and limbic seizures. NPY is abundantly expressed in the dentate gyrus and is thought to modulate hippocampal excitability via activation of presynaptic Y2 receptors (Y2R). Here we demonstrate that NPY, and commonly used Y2R-preferring (NPY13–36) and Y5 receptor (Y5R)–preferring ([d-Trp32]NPY and hPP) peptide agonists, evoke similar levels of inhibition at excitatory CA3 synapses in hippocampal slices from wild-type control mice (WT). In contrast, NPYergic inhibition of excitatory CA3 synaptic transmission is absent in mice lacking the Y5R subtype (Y5R KO). In both analyses of evoked population spike activity and spontaneous excitatory postsynaptic synaptic currents (EPSCs), NPY agonists induced powerful inhibitory effects in all hippocampal slices from WT mice, whereas these peptides had no effect in slices from Y5R KO mice. In slices from WT mice, NPY (and NPY receptor–preferring agonists) reduced the frequency of spontaneous EPSCs but had no effect on sEPSC amplitude, rise time, or decay time. Furthermore, NPYergic modulation of spontaneous EPSCs in WT mice was mimicked by bath application of a novel Y5R-selective peptide agonist ([cpp]hPP) but not the selective Y2R agonist ([ahx5–24]NPY). In situ hybridization was used to confirm the presence of NPY, Y2, and Y5 mRNA in the hippocampus of WT mice and the absence of Y5R in knockout mice. These results suggest that the Y5 receptor subtype, previously believed to mediate food intake, plays a critical role in modulation of hippocampal excitatory transmission at the hilar-to-CA3 synapse in the mouse. more...

Kainate receptor agonists depress transmitter release at several synapses in the hippocampus. Distinct mechanisms appear to underlie this phenomenon at different synapses. Recently, it has emerged that presynaptic kainate receptors can also potentiate the release of both GABA and glutamate and that axonal kainate receptors can trigger ectopic action potentials in interneurons. Because synaptically released glutamate mimics many of the actions of exogenous agonists, presynaptic kainate receptors potentially play an extensive role in hippocampal signaling. more...

In many vertebrate CNS synapses, the neurotransmitter glutamate activates postsynaptic non- N-methyl-d-aspartate (NMDA) and NMDA receptors. Since their biophysical properties are quite different, the time course of excitatory postsynaptic currents (EPSCs) depends largely on the relative contribution of their activation. To investigate whether the activation of the two receptor subtypes is affected by the synaptic interaction in the inner plexiform layer (IPL) of the mouse retina, we analyzed the properties of the light-evoked responses ofon-cone bipolar cells and on-transient amacrine cells in a retinal slice preparation. on-transient amacrine cells were whole cell voltage-clamped, and the glutamatergic synaptic input from bipolar cells was isolated by a cocktail of pharmacological agents (bicuculline, strychnine, curare, and atropine). Direct puff application of NMDA revealed the presence of functional NMDA receptors. However, the light-evoked EPSC was not significantly affected byd(−)-2-amino-5-phosphonopentanoic acid (d-AP5), but suppressed by 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) or 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466). These results indicate that the light-evoked EPSC is mediated mainly by AMPA receptors under this condition. Since bipolar cells have GABACreceptors at their terminals, it has been suggested that bipolar cells receive feedback inhibition from amacrine cells. Application of (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), a specific blocker of GABACreceptors, suppressed both the GABA-induced current and the light-evoked feedback inhibition observed in on-cone bipolar cells and enhanced the light-evoked EPSC of on-transient amacrine cells. In the presence of TPMPA, the light-evoked EPSC of amacrine cells was composed of AMPA and NMDA receptor-mediated components. Our results suggest that photoresponses of on-transient amacrine cells in the mouse retina are modified by the activation of presynaptic GABACreceptors, which may control the extent of glutamate spillover. more...

The high concentration in brain of unbound l-glutamic acid (in its anionic form, l-glutamate) fuelled considerable speculation as to its role in central nervous function more than 50 years ago. Claims in the 1940s that it could improve cognitive acuity in patients with mental impairment were particularly intriguing, though later refuted. In the early 1950s Hayashi [(1954) Keio J. Med. 3, 183–192] found that l-glutamate could cause convulsions and proposed that it might be a central synaptic transmitter. Soon thereafter, Curtis and colleagues [Curtis, Phillis and Watkins (1959) Nature (London) 183, 611] showed that l-glutamate depolarized and excited central neurons, as expected for an excitatory transmitter; however, various aspects of the action of l-glutamate seemed to argue strongly against a transmitter function. This negative view prevailed for some 20 years, before compelling evidence for such a role was adduced. Over the last two decades, extensive research has revealed a host of glutamate receptor subtypes, subserving several different functions in excitatory synaptic transmission. This paper gives a very brief and personal overview of the development of the field over the last 50 years from a mainly pharmacological standpoint. more...

We tested the effects of the acetylcholinesterase inhibitor eserine (10 mu M), an indicator of the activity of endogenous ACh, on the generation of epileptiform discharges during blockade of inhibitory GABA(A)-mediated potentials by bicuculline (10 mu M), in the CA3 area of hippocampal slices from postnatal days 4-20 (P4-P20) immature and adult rats. Eserine provoked or significantly increased the frequency of spontaneous synchronous epileptiform discharges, in 6/22 (27%) P4-P10 slices, 34/35 P11-P20 slices and 18/18 adult slices, an epileptogenic effect. Ln immature slices, spontaneous discharges showed a stable frequency throughout perfusion with eserine, while in 5/11 adult slices an initial fast frequency was followed by a slower steady-state one. The cholinergic agonist carbachol (CCh, 25 mu M) provoked only transient or no spontaneous synchronous discharges in adult slices (n = 8), thus suggesting that massive activation of cholinergic receptors may lead to suppression of epileptiform activity in adult brain. Stimulus-induced excitatory CA3 responses, were depressed by eserine in approximately half of 20 P4-P10, 45 P11-P20 and 11 adult slices. The depression consisted of a decrease in the amplitude, duration, and number of population spikes of the field potentials by about 30%, a minor neuroprotective effect, which did not change with maturation. The different developmental profiles of the epileptogenic and neuroprotective effects of endogenous ACh suggest that they are mediated by different mechanisms. These experiments demonstrate that, endogenous aCh is sufficient to induce epileptogenesis during a decrease or failure of GABAergic inhibition, in both greater than or equal to P10 immature and in adult hippocampus. We therefore suggest that clinical or behavioral conditions which raise the concentration of endogenous ACh may lower the threshold to seizures. (C) 1999 Elsevier Science B.V. All rights reserved. Brain Res more...

Blockade of hippocampal long-term potentiation by sustained tetanic stimulation near the recording site. Specific patterns of electrical stimulation trigger several forms of synaptic plasticity in hippocampal pyramidal cells, including a long-term potentiation (LTP) of excitatory synaptic transmission. I investigated the effect of commonly used stimulation protocols at different distances from the recording site. Sustained electrical stimulation (100 Hz, 1 s) delivered close to the recording site prevented LTP induction; the same stimulation from a second electrode placed farther away subsequently produced LTP at the same recording site. Strong stimulation near the recording site could also interfere with LTP triggered from a distal site. In contrast to sustained high-frequency stimulation, intermittent stimulation (θ burst pattern) delivered close to the recording site produced normal LTP. These data support the hypothesis that strong stimulation releases a factor that acts locally to prevent LTP. more...