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NMDA-type glutamate receptors are heterotetrameric complexes composed of two GluN1 and two GluN2 subunits. The precise composition of the GluN2 subunits determines the channel's biophysical properties and influences its interaction with postsynaptic scaffolding proteins and signaling molecules involved in synaptic physiology and plasticity. The precise regulation of NMDAR subunit composition at synapses is crucial for proper synaptogenesis, neuronal circuit development, and synaptic plasticity, a cellular model of memory formation. In the forebrain during early development, NMDARs contain solely the GluN2B subunit, which is necessary for proper synaptogenesis and synaptic plasticity. In rodents, GluN2A subunit expression begins in the second postnatal week, replacing GluN2B-containing NMDARs at synapses in an activity- or sensory experience-dependent process. This switch in NMDAR subunit composition at synapses alters channel properties and reduces synaptic plasticity. The molecular mechanism regulating the switch remains unclear. We have investigated the role of activity-dependent internalization of GluN2B-containing receptors in shaping synaptic NMDAR subunit composition. Using molecular, pharmacological, and electrophysiological approaches in cultured organotypic hippocampal slices from rats of both sexes, we show that the process of incorporating GluN2A-containing NMDAR receptors requires activity-dependent internalization of GluN2B-containing NMDARs. Interestingly, blockade of GluN2A synaptic incorporation was associated with impaired potentiation of AMPA-mediated synaptic transmission, suggesting a potential coupling between the trafficking of AMPARs into synapses and that of GluN2A-containing NMDARs. These insights contribute to our understanding of the molecular mechanisms underlying synaptic trafficking of glutamate receptors and synaptic plasticity. They may also have implications for therapeutic strategies targeting NMDAR function in neurological disorders., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Fragile X autosomal homolog 1 (FXR1), a member of the fragile X messenger riboprotein 1 family, has been linked to psychiatric disorders including autism and schizophrenia. Parvalbumin (PV) interneurons play critical roles in cortical processing and have been implicated in FXR1-linked mental illnesses. Targeted deletion of FXR1 from PV interneurons in mice has been shown to alter cortical excitability and elicit schizophrenia-like behavior. This indicates that FXR1 regulates behaviorally relevant electrophysiological functions in PV interneurons. We therefore expressed a genetically encoded hybrid voltage sensor in PV interneurons and used voltage imaging in slices of mouse somatosensory cortex to assess the impact of targeted FXR1 deletion. These experiments showed that PV interneurons lacking FXR1 had excitatory synaptic potentials with larger amplitudes and shorter latencies compared with wild type. Synaptic potential rise-times, decay-times, and half-widths were also impacted to degrees that varied between cortical layer and synaptic input. Thus, FXR1 modulates the responsiveness of PV interneurons to excitatory synaptic inputs. This will enable FXR1 to control cortical processing in subtle ways, with the potential to influence behavior and contribute to psychiatric dysfunction., Competing Interests: The authors declare no competing financial interests., (Copyright © 2025 Scheuer et al.)

There are various forms of stress including; physical, psychological and social stress. Exposure to physical stress can lead to physical sensations (e.g. hyperalgesia) and negative emotions including anxiety and depression in animals and humans. Recently, our studies in mice have shown that acute physical stress induced by the elevated open platform (EOP) can provoke long-lasting mechanical hypersensitivity. This effect appears to be related to activity in the anterior cingulate cortex (ACC) at the synaptic level. Indeed, EOP exposure induces synaptic plasticity in layer II/III pyramidal neurons from the ACC. However, it is still unclear whether or not EOP exposure alters intrinsic properties and synaptic transmission in layer V pyramidal neurons. This is essential because these neurons are known to be a primary output to subcortical structures which may ultimately impact the behavioral stress response. Here, we studied both intrinsic properties and excitatory/inhibitory synaptic transmission by using whole-cell patch-clamp method in brain slice preparations. The EOP exposure did not change intrinsic properties including resting membrane potentials and action potentials. In contrast, EOP exposure suppressed the frequency of miniature and spontaneous excitatory synaptic transmission with an alteration of kinetics of AMPA/GluK receptors. EOP exposure also reduced evoked synaptic transmission induced by electrical stimulation. Furthermore, we investigated projection-selective responses of the mediodorsal thalamus to the layer V ACC neurons. EOP exposure produced short-term depression in excitatory synaptic transmission on thalamo-ACC projections. These results suggest that the EOP stress provokes abnormal excitatory synaptic transmission in layer V pyramidal neurons of the ACC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Anxiety is an emotional response to a potential threat. It is characterized by worry, feelings of tension, and physical changes. Trinucleotide repeat containing adaptor 6A (TNRC6A) binds to argonaute (AGO) proteins and microRNAs to form the miRNA-induced silencing complex (miRISC), which mediates mRNA degradation, storage, and translational repression functions. However, whether TNRC6A is involved in anxiety regulation remains unknown. In this study, TNRC6A was downregulated in the prefrontal cortex (PFC) of mice exposed to acute restraint stress. Inhibition of TNRC6A in PFC induced anxious behaviour. RNA immunoprecipitation, RNA pull-down and real-time quantitative PCR revealed that TNRC6A directly binds to miR-21-3p and maintains its stability. Intriguingly, miR-21-3p was downregulated in the PFC of acute stress mice, whereas overexpression of miR-21-3p significantly reduced anxiety-like behaviour. Furthermore, miR-21-3p knockdown significantly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the PFC pyramidal neurons. Dual luciferase assay and western blotting confirmed that miR-21-3p binds to the 3 'UTR region of corticotropin-releasing factor (CRF) mRNA and regulates CRF and cAMP-response element binding protein (CREB) expression. These results confirm that low levels of TNRC6A in the PFC decrease the stability of miR-21-3p which promotes the up-regulation of CRF, leading to the development of anxiety-like behaviours. This research provides insight into a novel molecular mechanism by which TNRC6A regulates anxiety behaviour through the miR-21-3p/CRF signalling axis., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A high-fat diet (HFD)-induced obesity is associated with mental disorders in adolescence. However, the mechanisms underlying these associations remain unclear. In this study, we hypothesized that synaptic remodeling occurs in the ventral hippocampus (vHP) of obese mice. To investigate this, we established a postnatal model of HFD-induced obesity in mice and observed increased body weight, elevated plasma luteinizing hormone and testosterone levels, premature puberty, and enhanced anxiety-like behavior in male subjects. We also examined the effect of HFD on the c-Fos protein expression in the ventral dentate gyrus (vDG) and explored the influence of intracerebroventricular (i.c.v) oxytocin injections on HFD-induced anxiety. Our results indicated an increase in c-Fos-positive cells in the vDG following HFD consumption. Additionally, we recorded the spontaneous synaptic activity of miniature excitatory postsynaptic currents (mEPSCs) in the vDG. Notably, HFD resulted in an elevated mEPSC frequency without affecting mEPSC amplitude. Subsequently, investigations demonstrated that i.c.v oxytocin injections reversed anxiety-like behavior induced by HFD. Moreover, the application of oxytocin in a bath solution reduced the mEPSC frequency in the vDG. These findings suggest that postnatal HFD intake induces synaptic dysfunction in the vDG, associated with the hyperactivity of vDG neurons, potentially contributing to the anxiety-like behavior in juvenile obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Glutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary DG cell type, granule cells (GCs). Numerous MC synapses are on GC proximal dendrites in the inner molecular layer (IML). However, field recordings of the GC excitatory postsynaptic potential (fEPSPs) have not been used to study this pathway selectively. Here we describe methods to selectively activate MC axons in the IML using mice with Cre recombinase expressed in MCs. Slices were made after injecting adeno-associated virus (AAV) encoding channelrhodopsin (ChR2) in the DG. In these slices, we show that fEPSPs could be recorded reliably in the IML in response to optogenetic stimulation of MC axons. Furthermore, fEPSPs were widespread across the septotemporal axis. However, fEPSPs were relatively weak because they were small in amplitude and did not elicit a significant population spike in GCs. They also showed little paired pulse facilitation. We confirmed the extracellular findings with patch clamp recordings of GCs despite different recording chambers and other differences in methods. Together the results provide a simple method for studying MC activation of GCs and add to the evidence that this input is normally weak but widespread across the GC population., (© 2024 Wiley Periodicals LLC.)

Excessive activation of mTOR has been observed in the brains of mouse models for Dravet syndrome. We aim to confirm whether that the overactivation of mTOR contributes to the neuropathological changes leading to epileptogenesis and neurobehavior deficits to support a novel pharmacological therapeutic approach for Dravet syndrome. The mTOR inhibitor everolimus, as a clinical antiseizure medication, was utilized to investigate whether mTOR is involved in hyperthermia-induced seizures, anxiety-like, and autism-like behaviors, as well as to explore potential pathogenic mechanisms in Scn1a E1099X/+ mice, a model of Dravet syndrome. First, we found that mTOR signaling was upregulated in hippocampus tissues and neural cultures derived from Scn1a E1099X/+ mice prior to seizure onset. Behaviorally, everolimus increased the seizure threshold and improved anxiety-like and autism-like behaviors in Scn1a E1099X/+ mice. Electrophysiologically, everolimus reduced the frequency of spontaneous excitatory postsynaptic currents in dentate granule neurons from Scn1a E1099X/+ mice. Biochemically, everolimus prevented hyperthermia-induced phosphorylation of hippocampal S6 ribosome in hippocampus, and it delayed hyperthermia-induced increase of cytosolic Ca 2+ level in primary neuronal cultures derived from Scn1a E1099X/+ mice. Our results provide the evidence that overactivated mTOR as an important neuropathological change which regulates seizure threshold, impairments of neurobehavior, neuronal glutamatergic transmission and intracellular Ca 2+ levels in Scn1a E1099X/+ mice. Inhibition of mTOR is a potential pharmacological therapeutic approach., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Neural diversity can expand the encoding capacity of a circuitry. A striking example of diverse structure and function is presented by the afferent synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in the cochlea. Presynaptic active zones at the pillar IHC side activate at lower IHC potentials than those of the modiolar side that have more presynaptic Ca 2+ channels. The postsynaptic SGNs differ in their spontaneous firing rates, sound thresholds, and operating ranges. While a causal relationship between synaptic heterogeneity and neural response diversity seems likely, experimental evidence linking synaptic and SGN physiology has remained difficult to obtain. Here, we aimed at bridging this gap by ex vivo paired recordings of murine IHCs and postsynaptic SGN boutons with stimuli and conditions aimed to mimic those of in vivo SGN characterization. Synapses with high spontaneous rate of release ( SR ) were found predominantly on the pillar side of the IHC. These high SR synapses had larger and more temporally compact spontaneous EPSCs, lower voltage thresholds, tighter coupling of Ca 2+ channels and vesicular release sites, shorter response latencies, and higher initial release rates. This study indicates that synaptic heterogeneity in IHCs directly contributes to the diversity of spontaneous and sound-evoked firing of SGNs., Competing Interests: LJ, TM No competing interests declared, (© 2023, Jaime Tobón and Moser.)

Zebra finches undergo a gradual refinement of their vocalizations, transitioning from variable juvenile songs to the stereotyped song of adulthood. To investigate the neural mechanisms underlying song crystallization-a critical phase in this developmental process-we performed intracellular recordings in HVC (a premotor nucleus essential for song learning and production) of juvenile birds. We then compared these recordings to previously published electrophysiological data from adult birds. We found that HVC projection neurons in juvenile zebra finches during the song crystallization phase exhibited more variable spiking patterns compared to the precise bursting observed in adult HVC projection neurons. Additionally, subthreshold membrane potential fluctuations in juvenile neurons exhibited longer durations and larger amplitude excitatory postsynaptic potentials. These distinct temporal dynamics in HVC during song crystallization likely play a crucial role in the fine-tuning processes that shape the precise timing and structure of the mature zebra finch song., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures were approved by the Regierungspräsidium Oberbayern (VET 02-21-201), Landesamt für Gesundheit und Soziales (LAGeSo Berlin) (G 0225/16) at the Freie Universität Berlin. Adult male birds were acquired from Magnolia Bird Farm with informed consent. All maintenance and experimental procedures of adult birds were performed according to the guidelines established by the Institutional Animal Care and Use Committee at New York University Langone Medical Center. Song and neural data recordings from adult birds were performed in New York University Langone Medical Center. Data from adult birds was previously used in a publication Vallentin and Long [28] addressing a different research question. Juvenile male birds were acquired from the local zebra finch breeding colony in Max-Planck-Institute for Biological Intelligence, Seewiesen. All experiments involving juvenile birds were performed in Max-Planck-Institute for Biological Intelligence in Seewiesen. Consent to publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The prevalence of depressive disorders in women has been reported in many countries. However, the cellular mechanisms mediating such sex differences in stress susceptibility remain largely unknown. Previously, we showed that lateral habenula (LHb) neurons are more activated in female mice than in male mice by restraint stress. Given the important role of LHb in depressive disorders, we aimed to investigate the synaptic differences between male and female LHb and to examine the possible impact of the estrous cycle on neurotransmission in LHb. We found that the passive and active properties of LHb neurons differed according to the estrous cycle. Spontaneous excitatory postsynaptic currents exhibited higher amplitudes during the diestrus stage and lower frequencies in females than in males, whereas inhibitory postsynaptic currents showed no significant differences. Acute stress-induced hyperpolarization of resting membrane potentials (RMP) was observed in both sexes, with notable changes in female silent and tonic neurons. Stress exposure eliminated estrous cycle-dependent RMP differences and introduced cycle-specific excitability changes, especially in the metestrus and diestrus stages, suggesting that the hormonal cycle may set the synaptic tone of the LHb, thus modulating stress responses in females. Our study provides invaluable groundwork for understanding the detailed interaction between the estrous cycle and stress exposure in female LHb., (© 2024 Federation of American Societies for Experimental Biology.)

Mecamylamine, a noncompetitive blocker of nicotinic acetylcholine receptors (nAChRs), is the racemic mixture of two stereoisomers: S-(+)-mecamylamine (S-mec) and R-(-)-mecamylamine (R-mec), with distinct interactions with α4β2 nAChRs. It has been shown that mecamylamine increases glutamate release and excites serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN). In this study, we separately evaluated the effects of S-mec and R-mec on 5-HT neuron excitability. S-mec (3 μM) increased firing frequency by 40 %, while R-mec (3 μM) raised it by only 22 %. S-mec acts as a positive allosteric modulator on high-sensitivity (HS) α4β2 nAChRs at glutamate terminals, enhancing spontaneous excitatory postsynaptic currents (sEPSCs) in 5-HT neurons. Conversely, R-mec decreased sEPSCs by blocking HS α4β2 nAChRs and reduced GABA-mediated inhibitory currents (sIPSCs) by blocking α7 nAChRs at GABAergic terminals. These mechanisms make S-mec more effective than R-mec in enhancing 5-HT neuron firing. Moreover, combining S-mec with TC-2559, a selective agonist of HS α4β2 nAChRs, increased firing frequency by 65 %, exceeding the effect of S-mec alone. To validate these findings, we evaluated the antidepressant effects of S-mec (1 mg/kg) combined with TC-2559 or RJR-2403, another α4β2 nAChR agonist. This combination successfully reduced depression-like behaviors, suggesting a potential treatment strategy for patients resistant to conventional antidepressants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Functional recovery from brain damage, such as stroke, is a plastic process in the brain. The excitatory glutamate α -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) plays a crucial role in neuronal functions, and the synaptic trafficking of AMPAR is a fundamental mechanism underlying synaptic plasticity. We recently identified a collapsin response mediator protein 2 (CRMP2)-binding compound, edonerpic maleate, which augments rehabilitative training-dependent functional recovery from brain damage by facilitating experience-driven synaptic delivery of AMPARs. In animals recovering from cryogenic brain injury, a potential compensatory area adjacent to the injured region was observed, where the injection of CNQX, an AMPAR antagonist, significantly attenuated functional recovery. In the compensatory brain area of animals recovering from cryogenic injury, the administration of edonerpic maleate enhanced both excitatory and inhibitory synaptic inputs at pyramidal neurons. In contrast, recovered animals that did not receive the drug exhibited augmentation of only excitatory synaptic input. The threshold of picrotoxin-induced epileptic seizure in recovered animals without edonerpic maleate treatment was lower than in intact animals and recovered animals with edonerpic maleate. Thus, edonerpic maleate enhances motor function recovery from brain damage by balancing excitatory and inhibitory synaptic inputs, which helps prevent epileptic seizures during recovery., Competing Interests: Takuya Takahashi is one of the inventors of the patent application claiming the use of edonerpic maleate to enhance the functional recovery after brain damage [substance patent (WO03/03567, Alkyl ether derivatives or salts thereof) and use patent (WO/2015115582, post-nerve injury rehabilitation effect-enhancing agent comprising alkyl ether derivative or salt thereof)]. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Katsuno, Jitsuki, Ota, Yamanoue, Abe and Takahashi.)

Empathy, the ability to comprehend and share others' emotional states, impacts brain functions. This in vivo electrophysiological study explored the influence of chronic empathic stress on synaptic efficacy, as well as short-term and long-term plasticity at the Schaffer collateral/Commissural - CA1 synapses in the dorsal hippocampus of rats, in situations of social equality and inequality. Forty-eight male rats were randomized into six groups: control, pseudo-observer, pseudo-demonstrator, observer, demonstrator, and co-demonstrator (Co, Pse-Ob, Pse-De, Ob, De, Co-De) groups. Stress induction (2h/day, 21 days) was performed in situations of equality and inequality. Serum corticosterone levels, slope, amplitude, and area under the curve (AUC) of field excitatory postsynaptic potentials (fEPSPs) were assessed in the hippocampal CA1 area using input-output (I/O) functions, paired-pulse (PP) responses with different interpulse intervals (IPIs), and long-term potentiation (LTP) after high-frequency stimulation (HFS). The fEPSP slope, amplitude, and AUC significantly decreased in all stress groups, especially in the De and Pse-De groups. These parameters were significantly increased in the Co-De and Ob groups compared to the De group. Notably, the corticosterone levels strongly confirmed the electrophysiological findings. Chronic empathic stress could disrupt synaptic efficacy and plasticity in the CA1 area. Empathic stress, involving the presence of cagemates in situations of social equality and inequality, can modify long-term plasticity and serum corticosterone levels in demonstrators and co-demonstrators. Under empathic stress related to situations of inequality, freely moving observers may influence the demonstrators' stress experience. Therefore, the presence of a conspecific in the social inequality conditions had significant suppressive effects on long-term plasticity, while conversely, under equality conditions, long-term plasticity was favorably improved through social buffering., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical statement: The Research Ethics Committee of the Isfahan University of Medical Sciences (IR.MUI.AEC.1401.021) approved all experiments., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene lead to syndromic X-linked intellectual disability (XLID). Till now, the mechanism of intellectual disability caused by CUL4B mutation still needs to be elucidated. In this study, we used single-nucleus RNA sequencing (snRNA-seq) to investigate the impact of CUL4B deficiency on the transcriptional programs of diverse cell types. The results revealed that depletion of CUL4B resulted in impaired intercellular communication and elicited cell type-specific transcriptional changes relevant to synapse dysfunction. Golgi-Cox staining of brain slices and immunostaining of in vitro cultured neurons revealed remarkable synapse loss in CUL4B-deficient mice. Ultrastructural analysis via transmission electron microscopy (TEM) showed that the width of the synaptic cleft was significantly greater in CUL4B-deficient mice. Electrophysiological experiments found a decrease in the amplitude of AMPA receptor-mediated EPSCs in the hippocampal CA1 pyramidal neurons of CUL4B-deficient mice. These results indicate that depletion of CUL4B in mice results in morphological and functional abnormalities in synapses. Furthermore, behavioral tests revealed that depletion of CUL4B in the mouse nervous system results in impaired spatial learning and memory. Taken together, the findings of this study reveal the pathogenesis of neurological disorders associated with CUL4B mutations and promote the identification of therapeutic targets that can halt synaptic abnormalities and preserve memory in individuals., Competing Interests: Declarations. Ethics approval and consent to participate: All animal care and experiments were approved by the Animal Care and Use Committee of Shandong University School of Basic Medical Sciences (No. ECSBMSSDU2023-2-27). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The discovery of adult-born granule cells (aDGCs) in the dentate gyrus of the hippocampus has raised questions regarding how they develop, incorporate into the hippocampal circuitry, and contribute to learning and memory. Here, we used patch-clamp electrophysiology to investigate the intrinsic and synaptic excitability of mouse aDGCs as they matured, enabled by using a tamoxifen-induced genetic label to birth date the aDGCs at different animal ages. Importantly, we also undertook immunofluorescence studies of the expression of the immediate early gene Egr1 and compared these findings with the electrophysiology data in the same animals. We examined two groups of animals, with aDGC birthdating when the mice were 2 months and at 7-9 months of age. In both groups, cells 4 weeks old had lower thresholds for current-evoked action potentials than older cells but fired fewer spikes during long current pulses and responded more poorly to synaptic activation. aDGCs born in both 2 and 7-9-month-old mice matured in their intrinsic excitability and synaptic properties from 4-12 weeks postgenesis, but this occurred more slowly for the older age animals. Interestingly, this pattern of intrinsic excitability changes did not correlate with the pattern of Egr1 expression. Instead, the development of Egr1 expression was correlated with the frequency of spontaneous excitatory postsynaptic currents. These results suggest that in order for aDGCs to fully participate in hippocampal circuitry, as indicated by Egr1 expression, they must have developed enough synaptic input, in spite of the greater input resistance and reduced firing threshold that characterizes young aDGCs., (© 2024 The Author(s). Hippocampus published by Wiley Periodicals LLC.)

Background: The study examined the effects of 5-HT 7 receptor activation on GABAergic transmission within the dentate gyrus and plasticity at the glutamatergic perforant path input., Methods: Immunofluorescence imaging was performed using transverse hippocampal slices from transgenic mice expressing green fluorescent protein (GFP) under the Htr7 promoter. This was followed by whole-cell patch clamp electrophysiological recordings assessing the effects of pharmacologically activating 5-HT 7 receptors on spontaneous inhibitory postsynaptic currents recorded from dentate granule cells and hilar mossy cells-two glutamatergic neuron types present in the dentate gyrus. Extracellular recordings of field excitatory postsynaptic potentials were then performed to assess whether 5-HT 7 receptor activation influenced theta-burst stimulation-evoked plasticity of the perforant path synaptic input., Results: It was found that parvalbumin and somatostatin interneurons in the dentate gyrus expressed GFP, which suggests they express 5-HT 7 receptors. However, activation of 5-HT 7 receptors had no effect on GABAergic transmission targeting mossy cells or granule cells. There was also no effect of 5-HT 7 receptor activation on perforant path plasticity either with intact or blocked GABA A receptor signaling., Conclusion: The presence of 5-HT 7 receptors in a subset of parvalbumin and somatostatin interneurons in the mouse dentate gyrus could mean that they are involved in the inhibitory control of dentate gyrus activity. However, this potential effect was not evident in slice recordings of inhibitory transmission targeting principal cells and did not affect perforant path plasticity. Further experiments are needed to fully elucidate the functional role of these receptors in the dentate gyrus., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interests., (© 2024. The Author(s).)

The contribution of excitatory amino acids (AA) to ischemic brain injury has been widely described. In addition, we reported that a mixture of non-excitatory AA at plasmatic concentrations turns irreversible the depression of synaptic transmission caused by hypoxia. Here, we describe that the presence of seven non-excitatory AA (L-alanine, L-glutamine, glycine, L-histidine, L-serine, taurine, and L-threonine) during hypoxia provokes an irreversible neuronal membrane depolarization, after an initial phase of hyperpolarization. The collapse of the membrane potential correlates with a great increase in fiber volley amplitude. Nevertheless, we show that the presence of all seven AA is not necessary to cause the irreversible loss of fEPSP after hypoxia and that the minimal combination of AA able to provoke a solid, replicable effect is the mixture of L-alanine, glycine, L-glutamine, and L-serine. Additionally, L-glutamine seems necessary but insufficient to induce these harmful effects. We also prove that the deleterious effects of the AA mixtures on field potentials during hypoxia depend on both the identity and concentration of the individual AA in the mixture. Furthermore, we find that the accumulation of AA in the whole slice does not determine the outcome caused by the AA mixtures on the synaptic transmission during hypoxia. Finally, results obtained using pharmacological inhibitors and specific substrates of AA transporters suggest that system N and the alanine-serine-cysteine transporter 2 (ASCT2) participate in the non-excitatory AA-mediated deleterious effects during hypoxia. Thus, these AA transporters might represent therapeutical targets for the treatment of brain ischemia., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses plays an important role in cerebellum-related motor coordination and learning. LTD is induced by the conjunction of PF stimulation and climbing fiber (CF) stimulation or somatic PC depolarization, while long-term potentiation (LTP) is induced by PF stimulation alone. Therefore, it is considered that different types of stimulation induce different types of synaptic plasticity. However, we found that a small number of conjunctive stimulations (PF + somatic depolarization of PC) induced LTP, but did not induce LTD of a small size. This LTP was not associated with changes in paired-pulse ratio, suggesting postsynaptic origin. Additionally this LTP was dependent on nitric oxide. This LTP was also induced by a smaller number of physiological conjunctive PF and CF stimuli. These results suggested that a larger number or longer period of conjunctive stimulation is required to induce LTD by overcoming LTP. Ca 2+ transients at the PC dendritic region was measured by calcium imaging during LTD-inducing conjunctive stimulation. Peak amplitude of Ca 2+ transients increased gradually during repetitive conjunctive stimulation. Instantaneous peak amplitude was not different between the early phase and late phase, but the average amplitude was larger in the later phase than in the early phase. These results show that LTD overcomes LTP, and increased Ca 2+ integration or a number of stimulations is required for LTD induction., Competing Interests: Declarations. Ethics Approval: All experiments were approved by the Animal Research Committee of the National Center of Neurology and Psychiatry and in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s).)

In aging women, cognitive decline and increased risk of dementia have been associated with the cessation of ovarian hormones production at menopause. In the brain, presence of the key enzyme aromatase required for the synthesis of 17-β-estradiol (E2) allows for local production of E2 in absence of functional ovaries. Understanding how aromatase activity is regulated could help alleviate the cognitive symptoms. In female rodents, genetic or pharmacological reduction of aromatase activity over extended periods of time impair memory formation, decreases spine density, and hinders long-term potentiation (LTP) in the hippocampus. Conversely, increased excitatory neurotransmission resulting in rapid N-methyl-d-aspartic acid (NMDA) receptor activation rapidly promotes neuroestrogen synthesis. This rapid modulation of aromatase activity led us to address the hypothesis that acute neuroestrogens synthesis is necessary for LTP at the Schaffer collateral-cornu ammonis 1 (CA1) synapse in absence of circulating ovarian estrogens. To test this hypothesis, we did electrophysiological recordings of field excitatory postsynaptic potential (fEPSPs) in hippocampal slices obtained from ovariectomized mice. To assess the impact of neuroestrogens synthesis on LTP, we applied the specific aromatase inhibitor, letrozole, before the induction of LTP with a theta burst stimulation protocol. We found that blocking aromatase activity prevented LTP. Interestingly, exogenous E2 application, while blocking aromatase activity, was not sufficient to recover LTP in our model. Our results indicate the critical importance of rapid, activity-dependent local neuroestrogens synthesis, independent of circulating hormones for hippocampal synaptic plasticity in female rodents., (© 2024 The Author(s). Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Oxytocin receptor (OXTR) is expressed in a distinct population of neurons in the lateral septum (LS), among other brain regions, and is responsible for regulating various social and nonsocial behaviors, including reward processing, feeding, social memory, anxiety, and fear. The LS serves as a key link between the cortical and subcortical regions, yet the synaptic inputs that drive the OXTR-expressing LS neurons have not been characterized. Here, we established retrograde and anterograde viral tracing in the mouse brain to map the input connections of the intermediate part of the LS where OXTR neurons are concentrated. Utilizing pathway-specific optogenetic activation, we identified that the strongest cortical inputs to LS OXTR neurons are from the posteromedial amygdala cortex (PMCo) and the ventral hippocampus (vHipp). We further determined that these excitatory inputs exhibit distinct presynaptic and postsynaptic properties, with PMCo synapses displaying a lower release probability and smaller α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-to- N -methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic current (EPSC) ratio compared to vHipp synapses. Our results also demonstrated that both vHipp and PMCo inputs establish a direct excitatory and a disynaptic inhibitory circuit on LS OXTR neurons. These findings deepen our understanding of the synaptic control of LS OXTR neurons by cortical regions, carrying significant implications for the affective behaviors in which these neurons are involved. NEW & NOTEWORTHY This is the first identification and characterization of the cortical synaptic inputs that drive the oxytocin receptor (OXTR)-expressing neurons in the lateral septum (LS), which are involved in diverse affective behavior. The strongest cortical inputs to LS OXTR neurons are from the posteromedial amygdala cortex, an understudied cortical region that is beginning to gain prominence for its role in social behavior. The synapses from these projections show differences in properties compared to inputs from the ventral hippocampus.

Parvalbumin expressing interneurons (PV INs) are key players in the local inhibitory circuits and their developmental maturation coincides with the onset of adult-type network dynamics in the brain. Glutamatergic signaling regulates emergence of the unique PV IN phenotype, yet the receptor mechanisms involved are not fully understood. Here we show that GluK1 subunit containing kainate receptors (KARs) are necessary for development and maintenance of the neurochemical and functional properties of PV INs in the lateral and basal amygdala (BLA). Ablation of GluK1 expression specifically from PV INs resulted in low parvalbumin expression and loss of characteristic high firing rate throughout development. In addition, we observed reduced spontaneous excitatory synaptic activity at adult GluK1 lacking PV INs. Intriguingly, inactivation of GluK1 expression in adult PV INs was sufficient to abolish their high firing rate and to reduce PV expression levels, suggesting a role for GluK1 in dynamic regulation of PV IN maturation state. The PV IN dysfunction in the absence of GluK1 perturbed the balance between evoked excitatory vs. inhibitory synaptic inputs and long-term potentiation (LTP) in LA principal neurons, and resulted in aberrant development of the resting-state functional connectivity between mPFC and BLA. Behaviorally, the absence of GluK1 from PV INs associated with hyperactivity and increased fear of novelty. These results indicate a critical role for GluK1 KARs in regulation of PV IN function across development and suggest GluK1 as a potential therapeutic target for pathologies involving PV IN malfunction., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

A remaining challenge for genetically encoded voltage indicators (GEVIs) is the reliable detection of excitatory postsynaptic potentials (EPSPs). Here, we developed ASAP5 as a GEVI with enhanced activation kinetics and responsivity near resting membrane potentials for improved detection of both spiking and subthreshold activity. ASAP5 reported action potentials (APs) in vivo with higher signal-to-noise ratios than previous GEVIs and successfully detected graded and subthreshold responses to sensory stimuli in single two-photon trials. In cultured rat or human neurons, somatic ASAP5 reported synaptic events propagating centripetally and could detect ∼1-mV EPSPs. By imaging spontaneous EPSPs throughout dendrites, we found that EPSP amplitudes decay exponentially during propagation and that amplitude at the initiation site generally increases with distance from the soma. These results extend the applications of voltage imaging to the quantal response domain, including in human neurons, opening up the possibility of high-throughput, high-content characterization of neuronal dysfunction in disease., Competing Interests: Declaration of interests M.Z.L. is an inventor on a patent for the earlier ASAP1 voltage indicator., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) that are thought to facilitate maladaptive behaviors that interfere with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is functionally altered by chronic ethanol exposure. Our recent work identified dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7-10 days following ethanol exposure. CIE exposure significantly increased intrinsic excitability as well as spontaneous excitatory and inhibitory postsynaptic currents (sE/IPSCs) in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE exposure also increased the frequency of sEPSCs in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol exposure. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models"., Competing Interests: Declaration of Competing interest All authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Selective modifications in the expression or function of dendritic ion channels regulate the propagation of synaptic inputs and determine the intrinsic excitability of a neuron. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open upon membrane hyperpolarization and conduct a depolarizing inward current ( I h ). HCN channels are enriched in the dendrites of hippocampal pyramidal neurons where they regulate the integration of synaptic inputs. Synaptic plasticity can bidirectionally modify dendritic HCN channels in excitatory neurons depending on the strength of synaptic potentiation. In inhibitory neurons, however, the dendritic expression and modulation of HCN channels are largely unknown. In this study, we systematically compared the modulation of I h by synaptic potentiation in hippocampal CA1 pyramidal neurons and stratum radiatum (sRad) interneurons in mouse organotypic cultures. I h properties were similar in inhibitory and excitatory neurons and contributed to resting membrane potential and action potential firing. We found that in sRad interneurons, HCN channels were downregulated after synaptic plasticity, irrespective of the strength of synaptic potentiation. This suggests differential regulation of I h in excitatory and inhibitory neurons, possibly signifying their distinct role in network activity., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Herstel and Wierenga.)

Wnt signaling plays a role in synaptic plasticity, but the specific cellular events and molecular components involved in Wnt signaling-mediated synaptic plasticity are not well defined. Here, we report a change in the threshold required to induce synaptic plasticity that facilitates the induction of long-term potentiation (LTP) and inhibits the induction of long-term depression (LTD) during brief exposure to the noncanonical ligand Wnt-5a. Both effects are related to the metaplastic switch of hippocampal CA3-CA1 synaptic transmission, a complex mechanism underlying the regulation of the threshold required to induce synaptic plasticity and of synaptic efficacy. We observed an early increase in the amplitude of field excitatory postsynaptic potentials (fEPSPs) that persisted over time, including after washout. The first phase involves an increase in the fEPSP amplitude that is required to trigger a spontaneous second phase that depends on Jun N-terminal kinase (JNK) and N-methyl D-aspartate receptor (NMDAR) activity. These changes are prevented by treatment with secreted frizzled-related protein 2 (sFRP-2), an endogenous antagonist of Wnt ligands. Here, we demonstrate the contribution of Wnt-5a signaling to a process associated with metaplasticity at CA3-CA1 synapses that favors LTP over LTD., Competing Interests: Declarations Conflict of interest The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Ethical Approval The experimental procedures were approved by the Bioethical and Biosafety Committee of the Faculty of Biological Sciences of the Pontificia Universidad Católica de Chile and were conducted in accordance with the guidelines of the National Agency for Research and Development (ANID-Chile)., (© 2024. The Author(s).)

Snf7-3 is a crucial component of the endosomal sorting complexes required for transport (ESCRT) pathway, playing a vital role in endolysosomal functions. To elucidate the role of Snf7-3 in vivo, we developed conventional-like and conditional Snf7-3 knockout (KO) mouse models using a "Knockout-first" strategy. Conventional-like Snf7-3 KO mice showed significantly reduced Snf7-3 mRNA expression, and older mice (25-40 weeks) exhibited impaired social recognition and increased miniature excitatory postsynaptic currents (mEPSCs). Similarly, conditional KO mice aged 8-24 weeks, with Snf7-3 specifically deleted in forebrain excitatory neurons, displayed impaired object location memory and elevated mEPSC frequency. Consistently, Snf7-3 knockdown in cultured mouse hippocampal neurons led to increased densities of pre- and postsynaptic puncta, supporting the observed increase in mEPSC frequency. In addition, enhanced dendritic complexity was observed in the medial prefrontal cortex of these mice, indicating early synaptic disturbances. Our findings underscore the critical role of Snf7-3 in maintaining normal cognitive functions and social behaviors. The observed synaptic and behavioral deficits in both conventional-like and conditional KO mice highlight the importance of Snf7-3 in specific neuronal populations, suggesting that early synaptic changes could precede more pronounced cognitive impairments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Long-term changes of synaptic transmission can be induced by Hebbian-type homosynaptic mechanisms which require activation of both pre- and postsynapse and mediate associative learning, as well as by heterosynaptic mechanisms which do not require activation of the presynapse and are non-associative. The rules for induction of homosynaptic plasticity depend on the distance of the synapse from the soma. Does induction of heterosynaptic plasticity also depend on synaptic location? Here, we investigated heterosynaptic changes in pharmacologically isolated glutamatergic inputs arriving at either the proximal or the distal segments of the apical dendrite of layer 2/3 pyramidal neurons in rat visual cortex. We show that bursts of action potentials evoked without presynaptic stimulation induced potentiation of proximal inputs while having little effect on distal inputs. Such gradient of plasticity could be related to the attenuation of backpropagating action potentials along the dendrites. Thus, the location of the synapse on the dendritic tree is a determinant not only for homosynaptic but also for heterosynaptic plasticity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexey Malyshev reports financial support was provided by Russian Science Foundation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Olfactory behavior is highly plastic, and the olfactory tubercle (OT), a component of the olfactory cortex and ventral striatum, includes anteromedial (amOT) and lateral (lOT) domains with roles in attractive and aversive olfactory behavioral learning, respectively. However, the underlying properties of synaptic plasticity in these domains are incompletely understood. Synaptic plasticity is regulated by multiple signals including synaptic inputs and neuromodulators. Interestingly, the amOT domain exhibits high expression of various receptors for neuromodulators. We investigated synaptic plasticity in mouse OT slices by combining electrical stimulation and treatment with the appetite-promoting neuropeptide orexin, the receptors of which are highly expressed in the amOT. In both the amOT and lOT, one round of 2-Hz burst stimulation elicited short-term potentiation of the field excitatory postsynaptic potential, whereas three rounds of stimulation induced long-term potentiation (LTP) that persisted for 150 min. In the amOT, orexin-A induced LTP was blocked by the orexin receptor type 1 antagonist SB334867. Orexin-A also facilitated LTP induction in the amOT by one round of 2-Hz burst stimulation. By contrast, these effects were not observed in the lOT. These results highlighted the similarity and difference in synaptic plasticity between the OT domains and suggested that orexin facilitates synaptic plasticity in the amOT during olfactory learning processes such as food odor learning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Podder, Murata, Taniguchi, Shimizu and Yamaguchi.)

Experience- and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here, we demonstrate that the activity-dependent transcription factor myocyte enhancer factor 2C (MEF2C) is required in both presynaptic layer (L) 4 and postsynaptic L2/3 mouse (male and female) somatosensory (S1) cortical neurons for development of this specific synaptic connection. While postsynaptic deletion of Mef2c weakens L4 synaptic inputs, it has no effect on inputs from local L2/3, contralateral S1, or the ipsilateral frontal/motor cortex. Similarly, homozygous or heterozygous deletion of Mef2c in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Postsynaptic MEF2C is specifically required during an early postnatal, experience-dependent, period for L4 to L2/3 synapse function, and expression of transcriptionally active MEF2C (MEF2C-VP16) rescues weak L4 to L2/3 synaptic strength in sensory-deprived mice. Together, these results suggest that experience- and/or activity-dependent transcriptional activation of MEF2C promotes development of L4 to L2/3 synapses. Additionally, MEF2C regulates the expression of many pre- and postsynaptic genes in postnatal cortical neurons. Interestingly, MEF2C was necessary for activity-dependent expression of many presynaptic genes, including those that function in transsynaptic adhesion and neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The transition to alcohol use disorder (AUD) involves persistent neuroadaptations in executive control functions primarily regulated by the medial prefrontal cortex. However, the neurophysiological correlates to behavioral manifestations of AUD are not fully defined. The association between cortical neuroadaptations and behavioral manifestations of addiction was studied using a multi-symptomatic operant model based on the DSM-5 diagnostic criteria for AUD. This model aimed to characterize an AUD-vulnerable and AUD-resistant subpopulation of outbred male Wistar rats and was combined with electrophysiological measurements in the prelimbic cortex (PL). Mirroring clinical observations, rats exhibited individual variability in their vulnerability to develop AUD-like behavior, including motivation to seek for alcohol (crit 1), increased effort to obtain the substance (crit 2), and continued drinking despite negative consequences (crit 3). Only a small subset of rats met all the aforementioned AUD criteria (3 crit, AUD-vulnerable), while a larger fraction was considered AUD-resilient (0 crit). The development of AUD-like behavior was characterized by disruptions in glutamatergic synaptic activity, involving decreased frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and heightened intrinsic excitability in layers 2/3 PL pyramidal neurons. These alterations were concomitant with a significant impairment in the ability of mGlu2/3 receptors to negatively regulate glutamate release in the PL but not in downstream regions like the basolateral amygdala or nucleus accumbens core. In conclusion alterations in PL synaptic activity were strongly associated with individual addiction scores, indicating their role as potential markers of the behavioral manifestations linked to AUD psychopathology., (© 2024. The Author(s).)

Long-term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. IT and CT aerobic exercises started on postnatal day 56 in the offspring. Four weeks after IT and/or CT exercises, the offspring were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In the DG region, excitatory post synaptic potentials (EPSP) slope and population spike (PS) amplitude were measured. Sex differences in LTP were evident for control rats but not for VPA-exposed offspring. LTP was significantly smaller in VPA-exposed male offspring compared with control male rats. In contrast to males, there was no difference between VPA-exposed female offspring and control female rats. Interestingly, we observed a sex difference in the response to exercise between VPA-exposed male and female offspring. CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Prevailing hypotheses on the mechanisms of antidepressant action posit that antidepressants directly counteract deficiencies in major neurotransmitter signaling systems that underlie depression. The rapidly acting antidepressant ketamine has been postulated to correct excess glutamatergic signaling via glutamatergic antagonism leading to the rescue of neuronal structural deficits and reversal of behavioral symptoms. We studied this premise using systemic administration of the acetylcholinesterase inhibitor physostigmine, which has been shown to rapidly elicit a shorter-term period of depressed mood in humans via cholinergic mechanisms. We observed that physostigmine induces acute stress in tandem with long term depression of glutamate release in the hippocampus of mice. However, ketamine rapidly acts to re-establish glutamatergic synaptic efficacy via postsynaptic signaling and behaviorally masks the reduction in passive coping induced by physostigmine. These results underscore the divergence of synaptic signaling mechanisms underlying mood changes and antidepressant action and highlight how distinct synaptic mechanisms may underlie neuropsychiatric disorders versus their treatment., (© 2024. The Author(s).)

Changes in Hoffmann reflex (H-reflex) exhibit heterogeneity among patients with amyotrophic lateral sclerosis (ALS), likely due to phenotype diversity. Current knowledge primarily focuses on soleus H-reflex, which may demonstrate an initial increase before subsequent decline throughout the disease course. The main objective was to investigate other muscles, to determine whether H-reflex changes could be associated with patient phenotype (onset site, functional disabilities). Additional experiments were performed to elucidate the neurophysiological mechanisms underlying H-reflex modifications. In age- and sex-matched groups of control subjects and patients, we compared H-reflex recruitment curves in soleus, quadriceps, and forearm flexors. Additionally, we examined H-reflex and motor evoked potential (MEP) recruitment curves in quadriceps. Last, to assess potential changes in monosynaptic excitatory postsynaptic potentials (EPSPs) of both peripheral and cortical origins, we analyzed peristimulus time histograms (PSTHs) and peristimulus frequencygrams (PSFs) of single motor units, along with H-reflex occurrence after paired-pulse stimuli. The ratio between maximal amplitudes of H-reflex and direct motor response increased in all muscles, irrespective of disease onset, and was found positively correlated with exaggerated osteotendinous reflexes and spasticity but depressed in patients on riluzole. This finding was accompanied by a reduction in MEP size and no changes in PSTH, PSF, and paired-pulse H-reflex probability. It is speculated that spinal interneurons may compensate for potential depression of monosynaptic EPSPs in ALS. From a clinical perspective, although the added value of H-reflex to osteotendinous reflex evaluation may be limited, it can serve as a valuable quantitative biomarker of pyramidal dysfunction in clinical trials. NEW & NOTEWORTHY Without significant evidence of peripheral denervation, H-reflex enhancement appears to be a widespread phenomenon, regardless of disease onset site. This increase is likely associated with a decrease in inhibitory control over presynaptic transmission of the synapse between muscle group Ia afferents and motoneurons. Although the link to exaggerated osteotendinous reflexes and spasticity implies a restricted role in identifying a pyramidal syndrome, its quantitative aspect positions the H-reflex as a valuable biomarker in clinical trials.

Birth stress is a risk factor for psychiatric disorders and associated with exaggerated release of the stress hormone arginine vasopressin (AVP) into circulation and in the brain. In perinatal hippocampus, AVP activates GABAergic interneurons which leads to suppression of spontaneous network events and suggests a protective function of AVP on cortical networks during birth. However, the role of AVP in developing subcortical networks is not known. Here we tested the effect of AVP on the dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT, serotonin) system in male and female neonatal rats, since early 5-HT homeostasis is critical for the development of cortical brain regions and emotional behaviors. We show that AVP is strongly excitatory in neonatal DRN: it increases excitatory synaptic inputs of 5-HT neurons via V 1A receptors in vitro and promotes their action potential firing through a combination of its effect on glutamatergic synaptic transmission and a direct effect on the excitability of these neurons. Furthermore, we identified two major firing patterns of neonatal 5-HT neurons in vivo, tonic regular firing and low frequency oscillations of regular spike trains and confirmed that these neurons are also activated by AVP in vivo. Finally, we show that the sparse vasopressinergic innervation in neonatal DRN originates exclusively from cell groups in medial amygdala and bed nucleus of stria terminalis. Hyperactivation of the neonatal 5-HT system by AVP during birth stress may impact its own functional development and affect the maturation of cortical target regions, which may increase the risk for psychiatric conditions later on., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The CC chemokine ligand 2 (CCL2, also known as MCP-1) and its cognate receptor CCR2 have well-characterized roles in chemotaxis. CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excitability. However, the detailed molecular mechanism underlying this process remains largely unclear. In cultured hippocampal neurons, CCL2 application rapidly upregulated surface expression of GluA1, in a CCR2-dependent manner, assayed using SEP-GluA1 live imaging, surface GluA1 antibody staining, and electrophysiology. Using pharmacology and reporter assays, we further showed that CCL2 upregulated surface GluA1 expression primarily via Gα q - and CaMKII-dependent signaling. Consistently, using i.p. injection of lipopolysaccharide to induce neuroinflammation, we found upregulated phosphorylation of S831 and S845 sites on AMPA receptor subunit GluA1 in the hippocampus, an effect blocked in Ccr2 -/- mice. Together, these results provide a mechanism through which CCL2, and other secreted molecules that signal through G-protein coupled receptors, can directly regulate synaptic transmission., Competing Interests: Conflict of Interest: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s).)

Delta opioid receptors (DORs) are widely expressed throughout the central nervous system, including the cerebellum, where they play a regulatory role in neurogenesis. In the cerebellar cortex, Purkinje cells (PCs), the sole output neurons, receive glutamatergic synaptic input from parallel fibers (PFs)-the axonal extensions of granule cells-forming PF-PC synapses. However, the precise distribution of DORs within these synapses and their impact on synaptic transmission remain unclear. In this study, we utilized whole-cell patch-clamp recordings and neuropharmacological approaches to explore the effects of DORs activation on PF-PC synaptic transmission in the mouse cerebellar cortex and to elucidate the underlying mechanisms. We found that the selective DORs agonist DPDPE significantly reduced the amplitude and area under the curve (AUC) of PF-PC evoked excitatory postsynaptic currents (eEPSCs), accompanied by an increase in the paired-pulse ratio (PPR). This inhibitory effect was blocked by the DORs antagonist Naltrindole. Additionally, DPDPE decreased the frequency of PF-PC miniature excitatory postsynaptic currents (mEPSCs) without affecting their amplitude, indicating a presynaptic site of action. When the protein kinase A (PKA) inhibitor PKI was added to the internal solution of the recording electrode, it did not alter the DPDPE-induced suppression of PF-PC mEPSC frequency. However, this suppression was reversed by KT5720, a cell-permeable PKA-specific inhibitor. These findings suggest that DPDPE inhibits PF-PC synaptic transmission through the preferential activation of presynaptic DORs, with this process being dependent on the cyclic adenosine monophosphate (cAMP)-PKA signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Despite dysfunctional vasoactive intestinal polypeptide-positive interneurons (VIP-INs) being linked to the emergence of neurodevelopmental disorders, the temporal profile of VIP-IN functional maturation and cortical network integration remains unclear., Methods: Postnatal VIP-IN development was traced with patch clamp experiments in the somatosensory cortex of Vip-IRES-cre x tdTomato mice. Age groups were chosen during barrel field formation, before and after activation of main sensory inputs, and in adult animals (postnatal days (P) P3-4, P8-10, P14-16, and P30-36)., Results: Changes in passive and active membrane properties show a maturation towards accelerated signal integrations. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) showed progressive VIP-IN integration into cortical networks, likely via synaptogenesis: mEPSC frequency increased before P8-10, while mIPSC frequency increased at P14-16. Only mIPSC kinetics became accelerated, and the E/I ratio of synaptic inputs, defined as a ratio of mEPSC to mIPSC charge transfer, remained constant throughout the investigated developmental stages. Evoked (e)EPSCs and (e)IPSCs showed increased amplitudes, while only eIPSCs demonstrated faster kinetics. eEPSCs and eIPSCs revealed a paired-pulse facilitation by P14-16, indicating probably a decrease in the presynaptic release probability (p r ) and a paired-pulse depression in adulthood. eIPSCs also showed the latter, suggesting a decrease in p r for both signal transmission pathways at this time point., Conclusions: VIP-INs mature towards faster signal integration and pursue different strategies to avoid overexcitation. Excitatory and inhibitory synaptic transmission become stronger and shorter via different pre- and postsynaptic alterations, likely promoting the execution of active whisking., (© 2025 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

The primate dorsolateral prefrontal cortex (DLPFC) displays unique in vivo activity patterns, but how in vivo activity regulates DLPFC pyramidal neuron (PN) properties remains unclear. We assessed the effects of in vivo Kir2.1 overexpression, a genetic silencing tool, on synapses in monkey DLPFC PNs. We show for the first time that recombinant ion channel expression successfully modifies the excitability of primate cortex neurons, producing effects on synaptic properties apparently different from those in the rodent cortex.

The present study investigated metaplasticity-related mRNA expressions in valproic acid (VPA)-rats, focusing on the PI3K/AKT pathway. Wistar dams were treated with a single intraperitoneal injection of 600 mg/kg VPA or saline on embryonic day E12.5 or an equal volume of saline solution. Three behavioral tests were conducted on these males' offspring: grid-walking test, negative geotaxis test, and three-chamber social interaction test. Metaplasticity was induced in 60-day-old male progeny by giving high-frequency stimulation for 5 minutes following low-frequency stimulation to the perforant pathway. For the baseline stimulation protocol (n = 6), stimulation was delivered to the dentate gyrus at the previously determined stimulation intensity (0.33 Hz 0.175 msec 30 s) for 75 min. The percent change of slope of field excitatory postsynaptic potential (fEPSP) and amplitude of population spike were calculated 55-60 min after induction protocol. The mRNA levels of PI3K, PTEN, AKT, GSK-3β, and MAPT were measured in the hippocampus by using quantitative rt-PCR. We found that offspring of VPA-treated rats showed significantly impaired sensorimotor coordination, decreased sociability, impaired preference for social novelty, and reduced input-output curve of fEPSP slope, compared to control animals. Despite a similar metaplastic response, mRNA levels of genes of interest were similar but considerably down-regulated after induction in offspring of VPA-treated dams. Our study provides evidence that the induced expression of autism-related genes has evolved to enable an adaptation mechanism during metaplastic control of long-term potentiation., (© 2024 International Society for Developmental Neuroscience.)

The GluN3A subunit of N -methyl-D-aspartate receptors (NMDARs) plays an established role in synapse development, but its contribution to neural circuits in the adult brain is less clear. Recent work has demonstrated that in select cell populations, GluN3A assembles with GluN1 to form GluN1/GluN3A receptors that are insensitive to glutamate and instead serve as functional excitatory glycine receptors (eGlyRs). Our understanding of these eGlyRs, and how they contribute to intrinsic excitability and synaptic communication within relevant networks of the developing and the mature brain, is only beginning to be uncovered. Here, using male and female mice, we demonstrate that GluN3A subunits are enriched in the adult ventral hippocampus (VH), where they localize to synaptic and extrasynaptic sites and can assemble as functional eGlyRs on CA1 pyramidal cells. GluN3A expression was barely detectable in the adult dorsal hippocampus (DH). We also observed a high GluN2B content in the adult VH, characterized by slow NMDAR current decay kinetics and a high sensitivity to the GluN2B-containing NMDAR antagonist ifenprodil. Interestingly, the GluN2B enrichment in the adult VH was dependent on GluN3A as GluN3A deletion accelerated NMDAR decay and reduced ifenprodil sensitivity in the VH, suggesting that GluN3A expression can regulate the balance of conventional NMDAR subunit composition at synaptic sites. Lastly, we found that GluN3A knock-out also enhanced both NMDAR-dependent calcium influx and NMDAR-dependent long-term potentiation in the VH. Together, these data reveal a novel role for GluN3A and eGlyRs in the control of ventral hippocampal circuits in the mature brain., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from postmortem brains from patients with SCZ. In line with increased synapse density, patch-clamp analyses revealed markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons. Finally, MEA recordings from neuronal networks indicate increased strength of network activity, potentially in response to altered synaptic transmission and E-I balance in the co-cultures. In conclusion, our results suggest selective deregulation of neuronal activity in SCZ samples, providing evidence for altered synapse formation and synaptic transmission as a potential base for aberrant network synchronization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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-3α A687 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., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II + (CaMKII +) target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRN DA  → dBNST CaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression., (© 2024. The Author(s).)

While early-life adversity has been associated with a higher risk of developing chronic pain in adulthood, the cellular and molecular mechanisms by which chronic stress during the neonatal period can persistently sensitize developing nociceptive circuits remain poorly understood. Here, we investigate the effects of early-life stress (ELS) on synaptic integration and intrinsic excitability in dynorphin-lineage (DYN) interneurons within the adult mouse superficial dorsal horn (SDH), which are important for inhibiting mechanical pain and itch. The administration of neonatal limited bedding between postnatal days (P)2 and P9 evoked sex-dependent effects on spontaneous glutamatergic signaling, as female SDH neurons exhibited a higher amplitude of miniature excitatory postsynaptic currents (mEPSCs) after ELS, while mEPSC frequency was reduced in DYN neurons of the male SDH. Furthermore, ELS decreased the frequency of miniature inhibitory postsynaptic currents selectively in female DYN neurons. As a result, ELS increased the balance of spontaneous excitation versus inhibition (E:I ratio) in mature DYN neurons of the female, but not male, SDH network. Nonetheless, ELS weakened the total primary afferent-evoked glutamatergic drive onto adult DYN neurons selectively in females, without modifying afferent-evoked inhibitory signaling onto the DYN population. Finally, ELS failed to significantly change the intrinsic membrane excitability of mature DYN neurons in either males or females. Collectively, these data suggest that ELS exerts a long-term influence on the properties of synaptic transmission onto DYN neurons within the adult SDH, which includes a reduction in the overall strength of sensory input onto this important subset of inhibitory interneurons. PERSPECTIVE: This study suggests that chronic stress during the neonatal period influences synaptic function within adult spinal nociceptive circuits in a sex-dependent manner. These findings yield new insight into the potential mechanisms by which early-life adversity might shape the maturation of pain pathways in the central nervous system (CNS)., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

The basal ganglia play pivotal roles in motor control and cognitive functioning. These nuclei are embedded in an anatomical loop: cortex to basal ganglia to thalamus back to cortex. We focus here on an essential synapse for descending control, from cortical layer 5 (L5) onto the GABAergic spiny projection neurons (SPNs) of the caudoputamen (CP). We employed genetic labeling to distinguish L5 neurons from somatosensory (S1) and motor (M1) cortices in large volume serial electron microscopy and electrophysiology datasets to better detail these inputs. First, M1 and S1 synapses showed a strong preference to innervate the spines of SPNs and rarely contacted aspiny cells, which are likely to be interneurons. Second, L5 inputs commonly converge from both areas onto single SPNs. Third, compared to unlabeled terminals in CP, those labeled from M1 and S1 show ultrastructural hallmarks of strong driver synapses: They innervate larger spines that were more likely to contain a spine apparatus, more often had embedded mitochondria, and more often contacted multiple targets. Finally, these inputs also demonstrated driver-like functional properties: SPNs responded to optogenetic activation from S1 and M1 with large EPSP/Cs that depressed and were dependent on ionotropic but not metabotropic receptors. Together, our findings suggest that individual SPNs integrate driver input from multiple cortical areas with implications for how the basal ganglia relay cortical input to provide inhibitory innervation of motor thalamus., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

A whole-cell patch-clamp study was carried out to investigate membrane and synaptic properties of cholinergic interneurons in the striatum of aristaless-related homeobox gene (ARX) mutant mice. Brain slices were prepared from mice knocked in two types of ARX, P355L (PL) and 333ins (GCG)7 (GCG). The input resistance of cholinergic interneurons in PL or GCG mice was significantly smaller than that in wild type (WT), whereas resting membrane potential, threshold of action potentials, spontaneous firing rate, sag ratio or afterhyperpolarization of the mutant mice were not significantly different from those of WT mice. In GCG mice, NMDA/AMPA ratio of excitatory postsynaptic currents (EPSCs) evoked in cholinergic interneurons was significantly smaller than that in WT and PL mice, whereas the ratio between PL and WT mice was not significantly different. Although inhibitory effects induced by dopamine D2-like receptor activation on the inhibitory postsynaptic currents (IPSCs) were not significantly different between WT and PL or GCG mice, increase in the paired pulse ratio of IPSCs by dopamine D2-like receptor activation was abolished in PL and GCG mice. The present results have found abnormalities of neuronal activities as well as its modulation in the basal ganglia in ARX mutant mice, clarifying basic mechanisms underlying related disorders., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Synaptic plasticity occurs via multiple mechanisms to regulate synaptic efficacy. Homeostatic and Hebbian plasticity are two such mechanisms by which neuronal synapses can be altered. Although these two processes are mechanistically distinct, they converge on downstream regulation of AMPA receptor activity to modify glutamatergic neurotransmission. However, much remains to be explored regarding how these two prominent forms of plasticity interact. Ketamine, a rapidly acting antidepressant, increases glutamatergic transmission via pharmacologically-induced homeostatic plasticity. Here, we demonstrate that Hebbian plasticity mechanisms are still intact in synapses that have undergone homeostatic scaling by ketamine after either systemic injection or perfusion onto hippocampal brain slices. We also investigated this relationship in the context of stress induced by chronic exposure to corticosterone (CORT) to better model the circumstances under which ketamine may be used as an antidepressant. We found that CORT induced an anhedonia-like behavioral phenotype in mice but did not impair long-term potentiation (LTP) induction. Furthermore, corticosterone exposure does not impact the intersection of homeostatic and Hebbian plasticity mechanisms, as synapses from CORT-exposed mice also demonstrated intact ketamine-induced plasticity and LTP in succession. These results provide a mechanistic explanation for how ketamine used for the treatment of depression does not impair the integrity of learning and memory processes encoded by mechanisms such as LTP., (© 2024. The Author(s).)

Climbing fibers, connecting the inferior olive and Purkinje cells, form the nervous system's strongest neural connection. These fibers activate after critical events like motor errors or anticipation of rewards, leading to bursts of excitatory postsynaptic potentials (EPSPs) in Purkinje cells. The number of EPSPs is a crucial variable when the brain is learning a new motor skill. Yet, we do not know what determines the number of EPSPs. Here, we measured the effect of nucleo-olivary stimulation on periorbital elicited climbing fiber responses through in-vivo intracellular Purkinje cell recordings in decerebrated ferrets. The results show that while nucleo-olivary stimulation decreased the probability of a response occurring at all, it did not reduce the number of EPSPs. The results suggest that nucleo-olivary stimulation does not influence the number of EPSPs in climbing fiber bursts., (© 2024. The Author(s).)

Responding to burst stimulation of parallel fibers (PFs), cerebellar Purkinje neurons (PNs) generate a convolved synaptic response displaying a fast excitatory postsynaptic current (EPSC Fast ) followed by a slow EPSC (EPSC Slow ). The latter is companied with a rise of intracellular Ca 2+ and critical for motor coordination. The genesis of EPSC Slow in PNs results from activation of metabotropic type 1 glutamate receptor (mGluR1), oligomerization of stromal interaction molecule 1 (STIM1) on the membrane of endoplasmic reticulum (ER) and opening of transient receptor potential canonical 3 (TRPC3) channels on the plasma membrane. Neuronal nitric oxide synthase (nNOS) is abundantly expressed in PFs and granule neurons (GNs), catalyzing the production of nitric oxide (NO) hence regulating PF-PN synaptic function. We recently found that nNOS/NO regulates the morphological development of PNs through mGluR1-regulated Ca 2+ -dependent mechanism. This study investigated the role of nNOS/NO in regulating EPSC Slow . Electrophysiological analyses showed that EPSC Slow in cerebellar slices of nNOS knockout (nNOS -/- ) mice was significantly larger than that in wildtype (WT) mice. Activation of mGluR1 in cultured PNs from nNOS -/- mice evoked larger TRPC3-channel mediated currents and intracellular Ca 2+ rise than that in PNs from WT mice. In addition, nNOS inhibitor and NO-donor increased and decreased, respectively, the TRPC3-current and Ca 2+ rise in PNs. Moreover, the NO-donor effectively decreased TRPC3 currents in HEK293 cells expressing WT STIM1, but not cells expressing a STIM1 with cysteine mutants. These novel findings indicate that nNOS/NO inhibits TRPC3-containig channel mediated cation influx during EPSC Slow , at least in part, by S-nitrosylation of STIM1., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Excitatory glutamatergic NMDA receptors (NMDARs) are key regulators of spinal pain processing, and yet the biophysical properties of NMDARs in dorsal horn nociceptive neurons remain poorly understood. Despite the clinical implications, it is unknown whether the molecular and functional properties of synaptic NMDAR responses are conserved between males and females or translate from rodents to humans. To address these translational gaps, we systematically compared individual and averaged excitatory synaptic responses from lamina I pain-processing neurons of adult Sprague-Dawley rats and human organ donors, including both sexes. By combining patch-clamp recordings of outward miniature excitatory postsynaptic currents with non-biased data analyses, we uncovered a wide range of decay constants of excitatory synaptic events within individual lamina I neurons. Decay constants of synaptic responses were distributed in a continuum from 1-20 ms to greater than 1000 ms, suggesting that individual lamina I neurons contain AMPA receptor (AMPAR)-only as well as GluN2A-, GluN2B- and GluN2D-NMDAR-dominated synaptic events. This intraneuronal heterogeneity in AMPAR- and NMDAR-mediated decay kinetics was observed across sex and species. However, we discovered an increased relative contribution of GluN2A-dominated NMDAR responses at human lamina I synapses compared with rodent synapses, suggesting a species difference relevant to NMDAR subunit-targeting therapeutic approaches. The conserved heterogeneity in decay rates of excitatory synaptic events within individual lamina I pain-processing neurons may enable synapse-specific forms of plasticity and sensory integration within dorsal horn nociceptive networks. KEY POINTS: Synaptic NMDA receptors (NMDARs) in spinal dorsal horn nociceptive neurons are key regulators of pain processing, but it is unknown whether their functional properties are conserved between males and females or translate from rodents to humans. In this study, we compared individual excitatory synaptic responses from lamina I pain-processing neurons of male and female adult Sprague-Dawley rats and human organ donors. Individual lamina I neurons from male and female rats and humans contain AMPA receptor-only as well as GluN2A, GluN2B- and GluN2D-NMDAR-dominated synaptic events. This may enable synapse-specific forms of plasticity and sensory integration within dorsal horn nociceptive networks. Human lamina I synapses have an increased relative contribution of GluN2A-dominated NMDAR responses compared with rodent synapses. These results uncover a species difference relevant to NMDAR subunit-targeting therapeutic approaches., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)