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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions and verbal communication, accompanied by symptoms of restricted and repetitive patterns of behavior or interest. Over the past 30 years, the morbidity of ASD has increased in most areas of the world. Although the pathogenesis of ASD is not fully understood, it has been associated with over 1000 genes or genomic loci, indicating the importance and complexity of the genetic mechanisms involved. This review focuses on the synaptic pathology of ASD and particularly on genetic variants involved in synaptic structure and functions. These include SHANK, NLGN, NRXN, FMR1, and MECP2 as well as other potentially novel genes such as CHD8, CHD2, and SYNGAP1 that could be core elements in ASD pathogenesis. Here, we summarize several pathological pathways supporting the hypothesis that synaptic pathology caused by genetic mutations may be the pathogenic basis for ASD. [ABSTRACT FROM AUTHOR]

AMPA receptors (AMPARs) are the main drivers of excitatory glutamatergic transmission in the brain, central to synaptic plasticity, and are key drug targets. However, AMPARs are expressed in virtually every neuron in the central nervous system and are activated with complex temporal dynamics, making it difficult to determine their functional roles with sufficient precision. Here we describe a cell specific, light‐controllable competitive antagonist for the AMPA receptor called MP‐GluAblock that combines the temporal precision of a photo‐switchable ligand with the spatial and cellular specificity of a genetically‐encoded membrane‐anchor protein. This tool could pave the way for controlling endogenous AMPARs in neural circuits with cellular, spatial, and temporal specificity. [ABSTRACT FROM AUTHOR]

AMPA receptors (AMPARs) are the main drivers of excitatory glutamatergic transmission in the brain, central to synaptic plasticity, and are key drug targets. However, AMPARs are expressed in virtually every neuron in the central nervous system and are activated with complex temporal dynamics, making it difficult to determine their functional roles with sufficient precision. Here we describe a cell specific, light‐controllable competitive antagonist for the AMPA receptor called MP‐GluAblock that combines the temporal precision of a photo‐switchable ligand with the spatial and cellular specificity of a genetically‐encoded membrane‐anchor protein. This tool could pave the way for controlling endogenous AMPARs in neural circuits with cellular, spatial, and temporal specificity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

It is widely acknowledged that microglia actively regulate synaptic function in the brain. Remarkably, much of our understanding regarding the role of microglia in synaptic regulation is derived from studies in acute brain slices. However, it is still uncertain to what extent the preparation and maintenance of acute slices can influence microglial function and whether microglial changes may affect synaptic transmission. In this study, we examined the impact of acute slice resting time on hippocampal CA1 microglia, by assessing morphological and functional parameters at two distinct time intervals. We report that after 4 h from slicing microglia undergo morphological, functional, and transcriptional changes, including a decrease in the number of branches and in their movement speed. Furthermore, microglia acquire a reactive phenotype, characterized by increased amplitude of outward rectifying K+ currents, increased expression of the pro-inflammatory cytokine Tnfα and altered expression of the microglial receptors Cx3cr1 and P2y12r. We also examined time-dependent changes of excitatory synaptic transmission in CA1 pyramidal neurons from acute hippocampal slices, reporting time-dependent decrease in both amplitude and frequency of postsynaptic currents (sEPSCs), along with a decrease in spine density. Noticeably, sEPSCs amplitude decrease was absent in slices prepared from PLX5622 microglia-depleted mice, suggesting that this time-dependent effect on synaptic transmission is microglia-dependent. Our findings highlight possible causal relation between microglia phenotypic changes in the hours following slice preparation and concomitant synaptic changes, pointing to the mechanisms of acute synaptic modulation, whose understanding is crucial for unraveling microglia-neurons interplay in nature. Furthermore, they emphasize the potential issues associated with experimental time windows in ex vivo samples. [ABSTRACT FROM AUTHOR]

Norepinephrine (NE) modulates synaptic transmission and long-term plasticity through distinct subtype adrenergic receptor (AR)-mediated-intracellular signaling cascades. However, the role of NE modulates glutamatergic long-term potentiation (LTP) in the hypothalamic paraventricular nucleus (PVN) magnocellular neuroendocrine cells (MNCs) is unclear. We here investigate the effect of NE on high frequency stimulation (HFS)-induced glutamatergic LTP in rat hypothalamic PVN MNCs in vitro, by whole-cell patch-clamp recording, biocytin staining and pharmacological methods. Delivery of HFS induced glutamatergic LTP with a decrease in N2/N1 ratio in the PVN MNCs, which was enhanced by application of NE (100 nM). HFS-induced LTP was abolished by the blockade of N-methyl-D-aspartate receptors (NMDAR) with D-APV, but it was rescued by the application of NE. NE failed to rescue HFS-induced LTP of MNCs in the presence of a selective β1-AR antagonist, CGP 20712. However, application of β1-AR agonist, dobutamine HCl rescued HFS-induced LTP of MNCs in the absence of NMDAR activity. In the absence of NMDAR activity, NE failed to rescue HFS-induced MNC LTP when protein kinase A (PKA) was inhibited by extracellular applying KT5720 or intracellular administration of PKI. These results indicate that NE activates β1-AR and triggers HFS to induce a novel glutamatergic LTP of hypothalamic PVN NMCs via the postsynaptic PKA signaling pathway in vitro in rats. [ABSTRACT FROM AUTHOR]

The trigeminal sensory system consists of the trigeminal nerve, the trigeminal ganglion, and the trigeminal sensory nuclei (the mesencephalic nucleus, the principal nucleus, the spinal trigeminal nucleus, and several smaller nuclei). Various sensory signals carried by the trigeminal nerve from the orofacial area travel into the trigeminal sensory system, where they are processed into integrated sensory information that is relayed to higher sensory brain areas. Thus, knowledge of the trigeminal sensory system is essential for comprehending orofacial pain. This review elucidates the individual nuclei that comprise the trigeminal sensory system and their synaptic transmission. Additionally, it discusses four types of orofacial pain and their relationship to the system. Consequently, this review aims to enhance the understanding of the mechanisms underlying orofacial pain. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Motor ability decline remains a major threat to the quality of life of the elderly. Although the later stages of aging co-exist with degenerative pathologies, the long process of aging is more complicated than a simple and gradual degeneration. To combat senescence and the associated late-stage degeneration of the neuromuscular system, it is imperative to examine changes that occur during the long process of aging. Prior to late-stage degeneration, age-induced changes in the neuromuscular system trigger homeostatic plasticity. This unique phenomenon may be important for the maintenance of the neuromuscular system during the early stages of aging. In this review, we will focus on age-induced changes in neurotransmission at the neuromuscular junction, providing the potential mechanisms responsible for these changes. The goal is to highlight these key elements and their role in regulating neurotransmission, facilitating future research efforts to combat late-stage degeneration in the neuromuscular system by preserving the functional and structural integrity of these elements prior to the late stage of aging. [ABSTRACT FROM AUTHOR]

Communication between neurons and glia significantly influences the development maturation, plasticity, and disease progressions of the nervous system. As a new signaling modality, extracellular vesicles display a diverse role for robust functional regulation of neurons through their protein and nucleic acid cargoes. This review highlights recent breakthroughs in the research of signaling mechanisms between glia and neurons mediated by extracellular vesicles that are important for neural development, axonal maintenance, synaptic functions, and disease progression in the mammalian nervous system. We will discuss the biological roles of extracellular vesicles released from neurons, astroglia, microglia, and oligodendroglia in the nervous system and their implications in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The vestibular hair cell receptors of anamniotes, designated Type II, are presynaptic to bouton endings of vestibular nerve distal neurites. An additional flask-shaped hair cell receptor, Type I, is present in amniotes, and communicates with a chalice-shaped afferent neuritic ending that surrounds the entire hair cell except its apical neck. Since the full repertoire of afferent fiber dynamics and sensitivities observed throughout the vertebrate phyla can be accomplished through Type II hair cell-bouton synapses, the functional contribution(s) of Type I hair cells and their calyces to vestibular performance remains a topic of great interest. The goal of the present study was to investigate electrical coupling between the Type I hair cell and its enveloping calyx in the mouse semicircular canal crista ampullaris. Since there are no gap junctions between these two cells, evidence for electrical communication would necessarily involve other mechanisms. Simultaneous recordings from the two cells of the synaptic pair were used initially to verify the presence of orthodromic quantal synaptic transmission from the hair cell to the calyx, and then to demonstrate bi-directional communication due to the slow accumulation of potassium ions in the synaptic cleft. As a result of this potassium ion accretion, the equilibrium potentials of hair cell conductances facing the synaptic cleft become depolarized to an extent that is adequate for calcium influx into the hair cell, and the calyx inner face becomes depolarized to a level that is near the threshold for spike initiation. Following this, paired recordings were again employed to characterize fast bi-directional electrical coupling between the two cells. In this form of signaling, cleft-facing conductances in both the hair cell and calyx increase, which strengthens their coupling. Because this mechanism relies on the cleft resistance, we refer to it as resistive coupling. We conclude that the same three forms of hair cell-calyceal transmission previously demonstrated in the turtle are present in the mammalian periphery, providing a biophysical basis for the exceptional temporal fidelity of the vestibular system. [ABSTRACT FROM AUTHOR]

Since their discovery nearly 30 years ago, fibroblast growth factor homologous factors (FHFs) are now known to control the functionality of excitable tissues through a range of mechanisms. Nervous and cardiac system dysfunctions are caused by loss‐ or gain‐of‐function mutations in FHF genes. The best understood 'canonical' targets for FHF action are voltage‐gated sodium channels, and recent studies have expanded the repertoire of ways that FHFs modulate sodium channel gating. Additional 'non‐canonical' functions of FHFs in excitable and non‐excitable cells, including cancer cells, have been reported over the past dozen years. This review summarizes and evaluates reported canonical and non‐canonical FHF functions. [ABSTRACT FROM AUTHOR]

The subiculum is a key region of the brain involved in the initiation of pathological activity in temporal lobe epilepsy, and local GABAergic inhibition is essential to prevent subicular‐originated epileptiform discharges. Subicular pyramidal cells may be easily distinguished into two classes based on their different firing patterns. Here, we have compared the strength of the GABAa receptor‐mediated inhibitory postsynaptic currents received by regular‐ vs. burst‐firing subicular neurons and their dynamic modulation by the activation of μ opioid receptors. We have taken advantage of the sequential re‐patching of the same cell to initially classify pyramidal neurons according to their firing patters, and then to measure GABAergic events triggered by the optogenetic stimulation of parvalbumin‐ and somatostatin‐expressing interneurons. Activation of parvalbumin‐expressing cells generated larger responses in postsynaptic burst‐firing neurons whereas the opposite was observed for currents evoked by the stimulation of somatostatin‐expressing interneurons. In all cases, events depended critically on ω‐agatoxin IVA‐ but not on ω‐conotoxin GVIA‐sensitive calcium channels. Optogenetic GABAergic input originating from both parvalbumin‐ and somatostatin‐expressing cells was reduced in amplitude following the exposure to a μ opioid receptor agonist. The kinetics of this pharmacological sensitivity was different in regular‐ vs. burst‐firing neurons, but only when responses were evoked by the activation of parvalbumin‐expressing neurons, whereas no differences were observed when somatostatin‐expressing cells were stimulated. In conclusion, our results show that a high degree of complexity regulates the organizing principles of subicular GABAergic inhibition, with the interaction of pre‐ and postsynaptic diversity at multiple levels. Key points: Optogenetic stimulation of parvalbumin‐ and somatostatin‐expressing interneurons (PVs and SOMs) triggers inhibitory postsynaptic currents (IPSCs) in both regular‐ and burst‐firing (RFs and BFs) subicular pyramidal cells.The amplitude of optogenetically evoked IPSCs from PVs (PV‐opto IPSCs) is larger in BFs whereas IPSCs generated by the light activation of SOMs (SOM‐opto IPSCs) are larger in RFs.Both PV‐ and SOM‐opto IPSCs critically depend on ω‐agatoxin IVA‐sensitive P/Q type voltage‐gated calcium channels, whereas no major effects are observed following exposure to ω‐conotoxin GVIA, suggesting no significant involvement of N‐type channels.The amplitude of both PV‐ and SOM‐opto IPSCs is reduced by the probable pharmacological activation of presynaptic μ opioid receptors, with a faster kinetics of the effect observed in PV‐opto IPSCs from RFs vs. BFs, but not in SOM‐opto IPSCs.These results help us understand the complex interactions between different layers of diversity regulating GABAergic input onto subicular microcircuits. [ABSTRACT FROM AUTHOR]

Circadian fluctuations in physiological setpoints are determined by the suprachiasmatic nucleus (SCN) which exerts control over many target structures within and beyond the hypothalamus via projections. The SCN, or central pacemaker, orchestrates synchrony between the external environment and the internal circadian mechanism. The resulting cycles in hormone levels and autonomic nervous system (ANS) activity provide precise messages to specific organs, adjusting, for example, their sensitivity to approaching hormones or metabolites. The SCN responds to both photic (light) and non-photic input. Circadian patterns are found in both heart rate and blood pressure, which are linked to daily variations in activity and autonomic nervous system activity. Variations in blood pressure are of great interest as several cardiovascular diseases such as stroke, arrhythmias, and hypertension are linked to circadian rhythm dysregulation. The disruption of normal day-night cycles, such as in shift work, social jetlag, or eating outside of normal hours leads to desynchronization of the central and peripheral clocks. This desynchronization leads to disorganization of the cellular processes that are normally driven by the interactions of the SCN and photic input. Here, we review autonomic system function and dysfunction due to regulation and interaction between different cardiorespiratory brain centers and the SCN, as well as social, lifestyle, and external factors that may impact the circadian control of blood pressure. [ABSTRACT FROM AUTHOR]

Artemisinin (ART) and its derivatives, collectively referred to as artemisinins (ARTs), have been approved for the treatment of malaria for decades. ARTs are converted into dihydroartemisinin (DHA), the only active form, which is reductive in vivo. In this review, we provide a brief overview of the neuroprotective potential of ARTs and the underlying mechanisms on several of the most common neurodegenerative diseases, particularly considering their potential application in those associated with cognitive and motor impairments including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). ARTs act as autophagy balancers to alleviate AD and PD. They inhibit neuroinflammatory responses by regulating phosphorylation of signal transduction proteins, such as AKT, PI3K, ERK, NF-κB, p38 MAPK, IκBα. In addition, ARTs regulate GABAergic signaling in a dose-dependent manner. Although they competitively inhibit the binding of gephyrin to GABAergic receptors, low doses of ARTs enhance GABAergic signaling. ARTs can also inhibit ferroptosis, activate the Akt/Bcl-2, AMPK, or ERK/CREB pathways to reduce oxidative stress, and maintain mitochondrial homeostasis, protecting neurons from oxidative stress injury. More importantly, ARTs structurally combine with and suppress β-Amyloid (A β) -induced neurotoxicity, reduce P-tau, and maintain O-GlcNAcylation/Phosphorylation balance, leading to relieved pathological changes in neurodegenerative diseases. Collectively, these natural properties endow ARTs with unique potential for application in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. Our study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, we demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS. [ABSTRACT FROM AUTHOR]

N-Methyl-D-aspartate receptors (NMDARs), encoded by GRIN genes, are ionotropic glutamate receptors playing a critical role in synaptic transmission, plasticity, and synapse development. Genome sequence analyses have identified variants in GRIN genes in patients with neurodevelopmental disorders, but the underlying disease mechanisms are not well understood. Here, we have created and evaluated a transgenic mouse line carrying a missense variant Grin2bL825V, corresponding to a de novo GRIN2B variant encoding GluN2B(L825V) found in a patient with intellectual disability (ID) and autismspectrum disorder (ASD). We used HEK293T cells expressing recombinant receptors and primary hippocampal neurons prepared from heterozygous Grin2bL825V/+ (L825V/+) and wild-type (WT) Grin2b+/+ (+/+) male and female mice to assess the functional impact of the variant. Whole-cell NMDAR currents were reduced in neurons from L825V/+ compared with +/+ mice. The peak amplitude of NMDAR-mediated evoked excitatory postsynaptic currents (NMDAR-eEPSCs) was unchanged, but NMDAR-eEPSCs in L825V/+ neurons had faster deactivation compared with +/+ neurons and were less sensitive to a GluN2B-selective antagonist ifenprodil. Together, these results suggest a decreased functional contribution of GluN2B subunits to synaptic NMDAR currents in hippocampal neurons from L825V/+ mice. The analysis of the GluN2B(L825V) subunit surface expression and synaptic localization revealed no differences compared with WT GluN2B. Behavioral testing of mice of both sexes demonstrated hypoactivity, anxiety, and impaired sensorimotor gating in the L825V/+ strain, particularly affecting males, as well as cognitive symptoms. The heterozygous L825V/+ mouse offers a clinically relevant model of GRIN2B-related ID/ASD, and our results suggest synaptic-level functional changes that may contribute to neurodevelopmental pathology. [ABSTRACT FROM AUTHOR]

The release of neurotransmitters (NTs) at central synapses is dependent on a cascade of protein interactions, specific to the presynaptic compartment. Among those dedicated molecules, the cytosolic complexins play an incompletely defined role as synaptic transmission regulators. Complexins are multidomain proteins that bind soluble N-ethylmaleimide sensitive factor attachment protein receptor complexes, conferring both inhibitory and stimulatory functions. Using systematic mutagenesis and comparing reconstituted in vitro membrane fusion assays with electrophysiology in cultured neurons from mice of either sex, we deciphered the function of the N-terminus of complexin (Cpx) II. The N-terminus (amino acid 1-27) starts with a region enriched in hydrophobic amino acids (1-12), which binds lipids. Mutants maintaining this hydrophobic character retained the stimulatory function of Cpx, whereas exchanges introducing charged residues perturbed both spontaneous and evoked exocytosis. Mutants in the more distal region of the N-terminal domain (amino acid 11-18) showed a spectrum of effects. On the one hand, mutation of residue A12 increased spontaneous release without affecting evoked release. On the other hand, replacing D15 with amino acids of different shapes or hydrophobic properties (but not charge) not only increased spontaneous release but also impaired evoked release. Most surprising, this substitution reduced the size of the readily releasable pool, a novel function for Cpx at mammalian synapses. Thus, the exact amino acid composition of the Cpx N-terminus fine-tunes the degree of spontaneous and evoked NT release. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) in rodents mimics the hypoxia‐induced elevation of blood pressure seen in individuals experiencing episodic breathing. The brainstem nucleus tractus solitarii (nTS) is the first site of visceral sensory afferent integration, and thus is critical for cardiorespiratory homeostasis and its adaptation during a variety of stressors. In addition, the paraventricular nucleus of the hypothalamus (PVN), in part through its nTS projections that contain oxytocin (OT) and/or corticotropin‐releasing hormone (CRH), contributes to cardiorespiratory regulation. Within the nTS, these PVN‐derived neuropeptides alter nTS activity and the cardiorespiratory response to hypoxia. Nevertheless, their contribution to nTS activity after CIH is not fully understood. We hypothesized that OT and CRH would increase nTS activity to a greater extent following CIH, and co‐activation of OT+CRH receptors would further magnify nTS activity. Our data show that compared to their normoxic controls, 10 days' CIH exaggerated nTS discharge, excitatory synaptic currents and Ca2+ influx in response to CRH, which were further enhanced by the addition of OT. CIH increased the tonic functional contribution of CRH receptors, which occurred with elevation of mRNA and protein. Together, our data demonstrate that intermittent hypoxia exaggerates the expression and function of neuropeptides on nTS activity. Key points: Episodic breathing and chronic intermittent hypoxia (CIH) are associated with autonomic dysregulation, including elevated sympathetic nervous system activity. Altered nucleus tractus solitarii (nTS) activity contributes to this response.Neurons originating in the paraventricular nucleus (PVN), including those containing oxytocin (OT) and corticotropin‐releasing hormone (CRH), project to the nTS, and modulate the cardiorespiratory system. Their role in CIH is unknown.In this study, we focused on OT and CRH individually and together on nTS activity from rats exposed to either CIH or normoxia control.We show that after CIH, CRH alone and with OT increased to a greater extent overall nTS discharge, neuronal calcium influx, synaptic transmission to second‐order nTS neurons, and OT and CRH receptor expression.These results provide insights into the underlying circuits and mechanisms contributing to autonomic dysfunction during periods of episodic breathing. [ABSTRACT FROM AUTHOR]

The spatial distribution of proteins and their arrangement within the cellular ultrastructure regulates the opening of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in response to glutamate release at the synapse. Fluorescence microscopy imaging revealed that the postsynaptic density (PSD) and scaffolding proteins in the presynaptic active zone (AZ) align across the synapse to form a trans-synaptic "nanocolumn," but the relation to synaptic vesicle release sites is uncertain. Here, we employ focused-ion beam (FIB) milling and cryoelectron tomography to image synapses under near-native conditions. Improved image contrast, enabled by FIB milling, allows simultaneous visualization of supramolecular nanoclusters within the AZ and PSD and synaptic vesicles. Surprisingly, membrane-proximal synaptic vesicles, which fuse to release glutamate, are not preferentially aligned with AZ or PSD nanoclusters. These synaptic vesicles are linked to the membrane by peripheral protein densities, often consistent in size and shape with Munc13, as well as globular densities bridging the synaptic vesicle and plasma membrane, consistent with prefusion complexes of SNAREs, synaptotagmins, and complexin. Monte Carlo simulations of synaptic transmission events using biorealistic models guided by our tomograms predict that clustering AMPARs within PSD nanoclusters increases the variability of the postsynaptic response but not its average amplitude. Together, our data support a model in which synaptic strength is tuned at the level of single vesicles by the spatial relationship between scaffolding nanoclusters and single synaptic vesicle fusion sites. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify key proteins of synaptic transmission in the cochlear nucleus (CN) that are involved in normal hearing, acoustic stimulation, and tinnitus. A gene list was compiled from the GeneCards database using the keywords "synaptic transmission" AND "tinnitus" AND "cochlear nucleus" (Tin). For comparison, two gene lists with the keywords "auditory perception" (AP) AND "acoustic stimulation" (AcouStim) were built. The STRING protein–protein interaction (PPI) network and the Cytoscape data analyzer were used to identify the top two high-degree proteins (HDPs) and their high-score interaction proteins (HSIPs), together referred to as key proteins. The top1 key proteins of the Tin-process were BDNF, NTRK1, NTRK3, and NTF3; the top2 key proteins are FOS, JUN, CREB1, EGR1, MAPK1, and MAPK3. Highly significant GO terms in CN in tinnitus were "RNA polymerase II transcription factor complex", "late endosome", cellular response to cadmium ion", "cellular response to reactive oxygen species", and "nerve growth factor signaling pathway", indicating changes in vesicle and cell homeostasis. In contrast to the spiral ganglion, where important changes in tinnitus are characterized by processes at the level of cells, important biological changes in the CN take place at the level of synapses and transcription. [ABSTRACT FROM AUTHOR]

The goal of this report is to explore how K2P channels modulate axonal excitability by using the crayfish ventral superficial flexor preparation. This preparation allows for simultaneous recording of motor nerve extracellular action potentials (eAP) and intracellular excitatory junctional potential (EJP) from a muscle fiber. Previous pharmacological studies have demonstrated the presence of K2P‐like channels in crayfish. Fluoxetine (50 µM) was used to block K2P channels in this study. The blocker caused a gradual decline, and eventually complete block, of motor axon action potentials. At an intermediate stage of the block, when the peak‐to‐peak amplitude of eAP decreased to ∼60%–80% of the control value, the amplitude of the initial positive component of eAP declined at a faster rate than that of the negative peak representing sodium influx. Furthermore, the second positive peak following this sodium influx, which corresponds to the after‐hyperpolarizing phase of intracellularly recorded action potentials (iAP), became larger during the intermediate stage of eAP block. Finally, EJP recorded simultaneously with eAP showed no change in amplitude, but did show a significant increase in synaptic delay. These changes in eAP shape and EJP delay are interpreted as the consequence of depolarized resting membrane potential after K2P channel block. In addition to providing insights to possible functions of K2P channels in unmyelinated axons, results presented here also serve as an example of how changes in eAP shape contain information that can be used to infer alterations in intracellular events. This type of eAP‐iAP cross‐inference is valuable for gaining mechanistic insights here and may also be applicable to other model systems. [ABSTRACT FROM AUTHOR]

Background: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. Results: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. Conclusions: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors. [ABSTRACT FROM AUTHOR]

Background and Purpose: Voltage sensitivity is a common feature of many membrane proteins, including some G‐protein coupled receptors (GPCRs). However, the functional consequences of voltage sensitivity in GPCRs are not well understood. Experimental approach: In this study, we investigated the voltage sensitivity of the post‐synaptic metabotropic glutamate receptor mGlu5 and its impact on synaptic transmission. Using biosensors and electrophysiological recordings in non‐excitable HEK293T cells or neurons. Key Results: We found that mGlu5 receptor function is optimal at resting membrane potentials. We observed that membrane depolarization significantly reduced mGlu5 receptor activation, Gq‐PLC/PKC stimulation, Ca2+ release and mGlu5 receptor‐gated currents through transient receptor potential canonical, TRPC6, channels or glutamate ionotropic NMDA receptors. Notably, we report a previously unknown activity of the NMDA receptor at the resting potential of neurons, enabled by mGlu5. Conclusions and Implications: Our findings suggest that mGlu5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions. [ABSTRACT FROM AUTHOR]

Neurons in the central nervous system communicate with each other by activating billions of tiny synaptic boutons distributed along their fine axons. These presynaptic varicosities are very crowded environments, comprising hundreds of synaptic vesicles. Only a fraction of these vesicles can be recruited in a single release episode, either spontaneous or evoked by action potentials. Since the seminal work by Fatt and Katz, spontaneous release has been modelled as a memoryless process. Nevertheless, at central synapses, experimental evidence indicates more complex features, including non‐exponential distributions of release intervals and power‐law behaviour in their rate. To describe these features, we developed a probabilistic model of spontaneous release based on Brownian motion of synaptic vesicles in the presynaptic environment. To account for different diffusion regimes, we based our simulations on fractional Brownian motion. We show that this model can predict both deviation from the Poisson hypothesis and power‐law features in experimental quantal release series, thus suggesting that the vesicular motion by diffusion could per se explain the emergence of these properties. We demonstrate the efficacy of our modelling approach using electrophysiological recordings at single synaptic boutons and ultrastructural data. When this approach was used to simulate evoked responses, we found that the replenishment of the readily releasable pool driven by Brownian motion of vesicles can reproduce the characteristic binomial release distributions seen experimentally. We believe that our modelling approach supports the idea that vesicle diffusion and readily releasable pool dynamics are crucial factors for the physiological functioning of neuronal communication. Key points: We developed a new probabilistic model of spontaneous and evoked vesicle fusion based on simple biophysical assumptions, including the motion of vesicles before they dock to the release site.We provide closed‐form equations for the interval distribution of spontaneous releases in the special case of Brownian diffusion of vesicles, showing that a power‐law heavy tail is generated.Fractional Brownian motion (fBm) was exploited to simulate anomalous vesicle diffusion, including directed and non‐directed motion, by varying the Hurst exponent.We show that our model predicts non‐linear features observed in experimental spontaneous quantal release series as well as ultrastructural data of synaptic vesicles spatial distribution.Evoked exocytosis based on a diffusion‐replenished readily releasable pool might explain the emergence of power‐law behaviour in neuronal activity. [ABSTRACT FROM AUTHOR]

Background: Spreading depression (SD) is an intriguing phenomenon characterized by massive slow brain depolarizations that affect neurons and glial cells. This phenomenon is repetitive and produces a metabolic overload that increases secondary damage. However, the mechanisms associated with the initiation and propagation of SD are unknown. Multiple lines of evidence indicate that persistent and uncontrolled opening of hemichannels could participate in the pathogenesis and progression of several neurological disorders including acute brain injuries. Here, we explored the contribution of astroglial hemichannels composed of connexin-43 (Cx43) or pannexin-1 (Panx1) to SD evoked by high-K+ stimulation in brain slices. Results: Focal high-K+ stimulation rapidly evoked a wave of SD linked to increased activity of the Cx43 and Panx1 hemichannels in the brain cortex, as measured by light transmittance and dye uptake analysis, respectively. The activation of these channels occurs mainly in astrocytes but also in neurons. More importantly, the inhibition of both the Cx43 and Panx1 hemichannels completely prevented high K+-induced SD in the brain cortex. Electrophysiological recordings also revealed that Cx43 and Panx1 hemichannels critically contribute to the SD-induced decrease in synaptic transmission in the brain cortex and hippocampus. Conclusions: Targeting Cx43 and Panx1 hemichannels could serve as a new therapeutic strategy to prevent the initiation and propagation of SD in several acute brain injuries. [ABSTRACT FROM AUTHOR]

Endocannabinoid signalling mediated by cannabinoid receptor 1 (CB1R, also known as CNR1) is critical for homeostatic neuromodulation of both excitatory and inhibitory synapses. This requires highly polarised axonal surface expression of CB1R, but how this is achieved remains unclear. We previously reported that the α-helical H9 domain in the intracellular C terminus of CB1R contributes to axonal surface expression by an unknown mechanism. Here, we show in rat primary neuronal cultures that the H9 domain binds to the endocytic adaptor protein SGIP1 to promote CB1R expression in the axonal membrane. Overexpression of SGIP1 increases CB1R axonal surface localisation but has no effect on CB1R lacking the H9 domain (CB1RΔH9). Conversely, SGIP1 knockdown reduces axonal surface expression of CB1R but does not affect CB1RΔH9. Furthermore, SGIP1 knockdown diminishes CB1R-mediated inhibition of presynaptic Ca2+ influx in response to neuronal activity. Taken together, these data advance mechanistic understanding of endocannabinoid signalling by demonstrating that SGIP1 interaction with the H9 domain underpins axonal CB1R surface expression to regulate presynaptic responsiveness. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurodegeneration disease. Physical activity is one of the most promising modifiable lifestyles that can be effective in slowing down the progression of AD at an early stage. Objective: Explore the molecular processes impaired in AD that were conversely preserved and enhanced by physical activity. Methods: Integrated transcriptomic analyses were performed in datasets that contain AD patients and elders with different degrees of physical activity. The changes of the hub genes were validated through analyzing another two datasets. The expression of the hub genes was further detected in the hippocampus and cortexes of APP/PS1 transgenic mice with or without physical activity by Quantitative polymerase chain reaction (qPCR). Results: Cross-comparison highlighted 195 DEGs displaying opposed regulation patterns between AD and high physical activity (HPA). The common DEGs were predominantly involved in synaptic vesicle recycling and synaptic transmission, largely downregulated in AD patients but upregulated in the elders with HPA. Two key modules and four hub genes that were related to synaptic vesicle turnover were obtained from the PPI network. The expression of these hub genes (SYT1, SYT4, SH3GL2, and AP2M1) was significantly decreased in AD transgenic mice and was reversed by HPA training. Conclusions: HPA may reverse AD pathology by upregulating a range of synaptic vesicle transport related proteins which might improve the efficiency of synaptic vesicle turnover and facilitate inter-neuronal information transfer. The study provides novel insights into the mechanisms underlining the protective effects of HPA on AD. [ABSTRACT FROM AUTHOR]

The hippocampus is essential for learning and memory, but it also plays an important role in regulating emotional behavior, as hippocampal excitability and plasticity affect anxiety and fear. Brain synaptic plasticity may be regulated by tissue inhibitor of matrix metalloproteinase 1 (TIMP1), a known protein inhibitor of extracellular matrix (ECM), and the expression of TIMP1 in the hippocampus can be induced by neuronal excitation and various stimuli. However, the involvement of Timp1 in fear learning, anxiety, and hippocampal synaptic function remains to be established. Our study of Timp1 function in vivo revealed that Timp1 knockout mice exhibit anxiety-like behavior but normal fear learning. Electrophysiological results suggested that Timp1 knockout mice showed hyperactivity in the ventral CA1 region, but the basic synaptic transmission and plasticity were normal in the Schaffer collateral pathway. Taken together, our results suggest that deletion of Timp1 in vivo leads to the occurrence of anxiety behaviors, but that Timp1 is not crucial for fear learning. [ABSTRACT FROM AUTHOR]

Background and Purpose: P2X4 receptors (P2X4R) are ligand gated cation channels that are activated by extracellular ATP released by neurons and glia. The receptors are widely expressed in the brain and have fractional calcium currents comparable with NMDA receptors. Although P2X4Rs have been reported to modulate synaptic transmission and plasticity, their involvement in shaping neuronal network activity remains to be elucidated. Experimental Approach: We investigated the effects of P2X receptors at network and synaptic level using local field potential electrophysiology, whole cell patch clamp recordings and calcium imaging in fast spiking parvalbumin positive interneurons (PVINs) in rat and mouse hippocampal slices. The stable ATP analogue ATPγS, selective antagonists and P2X4R knockout mice were used. Key Results: The P2XR agonist ATPγS reversibly decreased the power of gamma oscillations. This inhibition could be antagonized by the selective P2X4R antagonist PSB‐12062 and was not observed in P2X4−/− mice. The phasic excitatory inputs of CA3 PVINs were one of the main regulators of the gamma power. Associational fibre compound excitatory postsynaptic currents (cEPSCs) in CA3 PVINs were inhibited by P2X4R activation. This effect was reversible, dependent on intracellular calcium and dynamin‐dependent internalization of AMPA receptors. Conclusions and Implications: The results indicate that P2X4Rs are an important source of dendritic calcium in CA3 PVINs, thereby regulating excitatory synaptic inputs onto the cells and presumably the state of gamma oscillations in the hippocampus. P2X4Rs represent an effective target to modulate hippocampal network activity in pathophysiological conditions such as Alzheimer's disease and schizophrenia. [ABSTRACT FROM AUTHOR]

Aim: The Repressor Element‐1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections. Methods: We investigated excitatory and inhibitory synaptic transmission by patch‐clamp recordings in acute neocortical slices in a conditional knockout mouse model (RestGTi) in which Rest was deleted by delivering PHP.eB adeno‐associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0‐P1 pups. Results: We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity. Conclusion: The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro‐epileptogenic. [ABSTRACT FROM AUTHOR]

Glycoproteins are proteins that contain oligosaccharide chains. As widely distributed functional proteins in the body, glycoproteins are essential for cellular development, cellular function maintenance, and intercellular communication. Glycoproteins not only play a role in the cell and the membrane, but they are also secreted in the intercell. These secreted glycoproteins are critical to the central nervous system for neurodevelopment and synaptic transmission. More specifically, secreted glycoproteins play indispensable roles in neurite growth mediation, axon guiding, synaptogenesis, neuronal differentiation, the release of synaptic vesicles, subunit composition of neurotransmitter receptors, and neurotransmitter receptor trafficking among other things. Abnormal expressions of secreted glycoproteins in the central nervous system are associated with abnormal neuron development, impaired synaptic organization/transmission, and neuropsychiatric disorders. This article reviews the secreted glycoproteins that regulate neuronal development and synaptic function in the central nervous system, and the molecular mechanism of these regulations, providing reference for research about synaptic function regulation and related central nervous system diseases. [ABSTRACT FROM AUTHOR]

Recent evidence has demonstrated that the transsynaptic nanoscale organization of synaptic proteins plays a crucial role in regulating synaptic strength in excitatory synapses. However, the molecular mechanism underlying this transsynaptic nanostructure in inhibitory synapses still remains unclear and its impact on synapse function in physiological or pathological contexts has not been demonstrated. In this study, we utilized an engineered proteolysis technique to investigate the effects of acute cleavage of neuroligin- 2 (NL2) on synaptic transmission. Our results show that the rapid cleavage of NL2 led to impaired synaptic transmission by reducing both neurotransmitter release probability and quantum size. These changes were attributed to the dispersion of RIM1/2 and GABAA receptors and a weakened spatial alignment between them at the subsynaptic scale, as observed through superresolution imaging and model simulations. Importantly, we found that endogenous NL2 undergoes rapid MMP9- dependent cleavage during epileptic activities, which further exacerbates the decrease in inhibitory transmission. Overall, our study demonstrates the significant impact of nanoscale structural reorganization on inhibitory transmission and unveils ongoing modulation of mature GABAergic synapses through active cleavage of NL2 in response to hyperactivity. [ABSTRACT FROM AUTHOR]

The human PLAA gene encodes Phospholipase-A2-Activating-Protein (PLAA) involved in trafficking of membrane proteins. Through its PUL domain (PLAP, Ufd3p, and Lub1p), PLAA interacts with p97/VCP modulating synaptic vesicles recycling. Although few families carrying biallelic PLAA variants were reported with progressive neurodegeneration, consequences of monoallelic PLAA variants have not been elucidated. Using exome or genome sequencing we identified PLAA de-novo missense variants, affecting conserved residues within the PUL domain, in children affected with neurodevelopmental disorders (NDDs), including psychomotor regression, intellectual disability (ID) and autism spectrum disorders (ASDs). Computational and in-vitro studies of the identified variants revealed abnormal chain arrangements at C-terminal and reduced PLAA-p97/VCP interaction, respectively. These findings expand both allelic and phenotypic heterogeneity associated to PLAA-related neurological disorders, highlighting perturbed vesicle recycling as a potential disease mechanism in NDDs due to genetic defects of PLAA. [ABSTRACT FROM AUTHOR]

The presynaptic SNARE-complex regulator complexin (Cplx) enhances the fusogenicity of primed synaptic vesicles (SVs). Consequently, Cplx deletion impairs action potential-evoked transmitter release. Conversely, though, Cplx loss enhances spontaneous and delayed asynchronous release at certain synapse types. Using electrophysiology and kinetic modeling, we show that such seemingly contradictory transmitter release phenotypes seen upon Cplx deletion can be explained by an additional of Cplx in the control of SV priming, where its ablation facilitates the generation of a "faulty" SV fusion apparatus. Supporting this notion, a sequential two-step priming scheme, featuring reduced vesicle fusogenicity and increased transition rates into the faulty primed state, reproduces all aberrations of transmitter release modes and short-term synaptic plasticity seen upon Cplx loss. Accordingly, we propose a dual presynaptic function for the SNARE-complex interactor Cplx, one as a "checkpoint" protein that guarantees the proper assembly of the fusion machinery during vesicle priming, and one in boosting vesicle fusogenicity. [ABSTRACT FROM AUTHOR]

The comorbidity of chronic pain and depression poses tremendous challenges for the treatment of either one because they exacerbate each other with unknown mechanisms. As the posterior insular cortex (PIC) integrates multiple somatosensory and emotional information and is implicated in either chronic pain or depression, we hypothesize that the PIC and its projections may contribute to the pathophysiology of comorbid chronic pain and depression. We show that PIC neurons were readily activated bymechanical, thermal, aversive, and stressful and appetitive stimulation in naive and neuropathic pain male mice subjected to spared nerve injury (SNI). Optogenetic activation of PIC neurons induced hyperalgesia and conditioned place aversion in naive mice, whereas inhibition of these neurons led to analgesia, conditioned place preference (CPP), and antidepressant effect in both naive and SNI mice. Combining neuronal tracing, optogenetics, and electrophysiological techniques, we found that the monosynaptic glutamatergic projections from the PIC to the basolateral amygdala (BLA) and the ventromedial nucleus (VM) of the thalamus mimicked PIC neurons in pain modulation in naive mice; in SNI mice, both projections were enhanced accompanied by hyperactivity of PIC, BLA, and VM neurons and inhibition of these projections led to analgesia, CPP, and antidepressant-like effect. The present study suggests that potentiation of the PIC→BLA and PIC→VM projections may be important pathophysiological bases for hyperalgesia and depression-like behavior in neuropathic pain and reversing the potentiation may be a promising therapeutic strategy for comorbid chronic pain and depression. [ABSTRACT FROM AUTHOR]

Nerve injury induced microglia activation, which released inflammatory mediators and developed neuropathic pain. Picroside Ⅱ (PⅡ) attenuated neuropathic pain by inhibiting the neuroinflammation of the spinal dorsal horn; however, how it engaged in the cross talk between microglia and neurons remained ambiguous. This study aimed to investigate PⅡ in the modulation of spinal synaptic transmission mechanisms on pain hypersensitivity in neuropathic rats. We investigated the analgesia of PⅡ in mechanical and thermal hyperalgesia using the spinal nerve ligation (SNL)-induced neuropathic pain model and formalin-induced tonic pain model, respectively. RNA sequencing and network pharmacology were employed to screen core targets and signaling pathways. Immunofluorescence staining and qPCR were performed to explore the expression level of microglia and inflammatory mediator mRNA. The whole-cell patch–clamp recordings were utilized to record miniature excitatory postsynaptic currents in excitatory synaptic transmission. Our results demonstrated that the analgesic of PⅡ was significant in both pain models, and the underlying mechanism may involve inflammatory signaling pathways. PⅡ reversed the SNL-induced overexpression of microglia and inflammatory factors. Moreover, PⅡ dose dependently inhibited excessive glutamate transmission. Thus, this study suggested that PⅡ attenuated neuropathic pain by inhibiting excitatory glutamate transmission of spinal synapses, induced by an inflammatory response on microglia. [ABSTRACT FROM AUTHOR]

Neuronal timing with millisecond precision is critical for many brain functions such as sensory perception, learning and memory formation. At the level of the chemical synapse, the synaptic delay is determined by the presynaptic release probability (Pr) and the waveform of the presynaptic action potential (AP). For instance, paired-pulse facilitation or presynaptic long-term potentiation are associated with reductions in the synaptic delay, whereas paired-pulse depression or presynaptic long-term depression are associated with an increased synaptic delay. Parallelly, the AP broadening that results from the inactivation of voltage gated potassium (Kv) channels responsible for the repolarization phase of the AP delays the synaptic response, and the inactivation of sodium (Nav) channels by voltage reduces the synaptic latency. However, whether synaptic delay is modulated during depolarization-induced analogue–digital facilitation (d-ADF), a form of context-dependent synaptic facilitation induced by prolonged depolarization of the presynaptic neuron and mediated by the voltage-inactivation of presynaptic Kv1 channels, remains unclear. We show here that despite Pr being elevated during d-ADF at pyramidal L5-L5 cell synapses, the synaptic delay is surprisingly unchanged. This finding suggests that both Pr- and AP-dependent changes in synaptic delay compensate for each other during d-ADF. We conclude that, in contrast to other short- or long-term modulations of presynaptic release, synaptic timing is not affected during d-ADF because of the opposite interaction of Pr- and AP-dependent modulations of synaptic delay. [ABSTRACT FROM AUTHOR]

The preBötzinger complex (preBötC) and the Bötzinger complex (BötC) are interconnected neural circuits that are involved in the regulation of breathing in mammals. Fast inhibitory neurotransmission is known to play an important role in the interaction of these two regions. Moreover, the corelease of glycine and GABA has been described in the respiratory network, but the contribution of the individual neurotransmitter in different pathways remains elusive. In sagittal brainstem slices of neonatal mice, we employed a laser point illumination system to activate glycinergic neurons expressing channelrhodopsin-2 (ChR2). This approach allowed us to discern the contribution of glycine and GABA to postsynaptic currents of individual whole-cell clamped neurons in the preBötC and BötC through the application of glycine and GABA receptor-specific antagonists. In more than 90% of the recordings, both transmitters contributed to the evoked IPSCs, with the glycinergic component being larger than the GABAergic component. The GABAergic component appeared to be most prominent when stimulation and recording were both performed within the preBötC. Taken together, our data suggest that GABA–glycine cotransmission is the default mode in the respiratory network of neonatal mice with regional differences that may be important in tuning the network activity. [ABSTRACT FROM AUTHOR]

UBE3A is a common genetic factor in ASD etiology, and transgenic mice overexpressing UBE3A exhibit typical autistic-like behaviors. Because AMPA receptors (AMPARs) mediate most of the excitatory synaptic transmission in the brain, and synaptic dysregulation is considered one of the primary cellular mechanisms in ASD pathology, we investigate here the involvement of AMPARs in UBE3A-dependent ASD. We show that expression of the AMPAR GluA1 subunit is decreased in UBE3A-overexpressing mice, and that AMPAR-mediated neuronal activity is reduced. GluA1 mRNA is trapped in the nucleus of UBE3A-overexpressing neurons, suppressing GluA1 protein synthesis. Also, SARNP, an mRNA nuclear export protein, is downregulated in UBE3A-overexpressing neurons, causing GluA1 mRNA nuclear retention. Restoring SARNP levels not only rescues GluA1 mRNA localization and protein expression, but also normalizes neuronal activity and autistic behaviors in mice overexpressing UBE3A. These findings indicate that SARNP plays a crucial role in the cellular and behavioral phenotypes of UBE3A-induced ASD by regulating nuclear mRNA trafficking and protein translation of a key AMPAR subunit. Synopsis: Downregulation of SARNP, an mRNA nuclear export factor, leads to GluA1 mRNA nuclear retention in mice with UBE3A-dependent autistic-like behavior. This decreases GluA1 protein synthesis and AMPAR synaptic currents and promotes autistic behaviors. AMPA receptor expression and synaptic localization are downregulated in UBE3A-overexpressing ASD mice. GluA1 mRNA is retained in the nuclei of UBE3A-overexpressing neurons, suppressing GluA1 protein synthesis. SARNP, an mRNA nuclear export protein, is reduced in UBE3A-overexpressing neurons. Restoring SARNP rescues AMPAR expression, neuronal activity, and autistic behaviors in UBE3A-dependent ASD mice. Downregulation of SARNP, an mRNA nuclear export factor, leads to GluA1 mRNA nuclear retention in mice with UBE3A-dependent autistic-like behavior. This decreases GluA1 protein synthesis and AMPAR synaptic currents and promotes autistic behaviors. [ABSTRACT FROM AUTHOR]

Shellfish poisoning is a common food poisoning. To comprehensively characterize proteome changes in the whole brain due to shellfish poisoning, Tandem mass tag (TMT)-based differential proteomic analysis was performed with a low-dose chronic shellfish poisoning model in mice. A total of 6798 proteins were confidently identified, among which 123 proteins showed significant changes (fold changes of >1.2 or <0.83, p < 0.05). In positive regulation of synaptic transmission, proteins assigned to a presynaptic membrane (e.g., Grik2) and synaptic transmission (e.g., Fmr1) changed. In addition, altered proteins in nervous system development were observed, suggesting that mice suffered nerve damage due to the nervous system being activated. Ion transport in model mice was demonstrated by a decrease in key enzymes (e.g., Kcnj11) in voltage-gated ion channel activity and solute carrier family (e.g., Slc38a3). Meanwhile, alterations in transferase activity proteins were observed. In conclusion, these modifications observed in brain proteins between the model and control mice provide valuable insights into understanding the functional mechanisms underlying shellfish poisoning. [ABSTRACT FROM AUTHOR]

The dorsal nucleus of the lateral lemniscus (DNLL) is a GABAergic, reciprocally connected auditory brainstem structure that continues to develop postnatally in rodents. One key feature of the DNLL is the generation of a strong, prolonged, ionotropic, GABAA receptor‐mediated inhibition. Possible GABAB receptor‐mediated signalling is unexplored in the DNLL. Here, we used Mongolian gerbils of either sex to describe GABAB receptor‐mediated modulation of postsynaptic potassium currents and synaptic inputs in postnatal (P) animals of days 10/11 and 23–28. Throughout development, we observed the presence of a Baclofen‐activated GABAB receptor‐enhanced potassium outward conductance that is capable of suppressing action potential generation. In P10/11, old gerbils GABAB receptor activation enhances glutamatergic and suppresses ionotropic GABAergic synaptic transmission. During development, this differential modulation becomes less distinct, because in P22–28, old animals Baclofen‐activated GABAB receptors rather enhance ionotropic GABAergic synaptic transmission, whereas glutamatergic transmission is both enhanced and suppressed. Blocking GABAB receptors causes an increase in ionotropic GABAergic transmission in P10/11 old gerbils that was independent on stimulation frequency but depended on the type of short‐term plasticity. Together with the lack of Baclofen‐induced changes in the synaptic paired‐pulse ratio of either input type, we suggest that GABAB receptor‐mediated modulation is predominantly postsynaptic and activates different signalling cascades. Thus, we argue that in DNLL neurons, the GABAB receptor is a post‐synaptically located signalling hub that alters signalling cascades during development for distinct targets. [ABSTRACT FROM AUTHOR]

The intricate functionality of the vertebrate retina relies on the interplay between neurotransmitter activity and calcium (Ca2+) dynamics, offering important insights into developmental processes, physiological functioning, and disease progression. Neurotransmitters orchestrate cellular processes to shape the behavior of the retina under diverse circumstances. Despite research to elucidate the roles of individual neurotransmitters in the visual system, there remains a gap in our understanding of the holistic integration of their interplay with Ca2+ dynamics in the broader context of neuronal development, health, and disease. To address this gap, the present review explores the mechanisms used by the neurotransmitters glutamate, gamma-aminobutyric acid (GABA), glycine, dopamine, and acetylcholine (ACh) and their interplay with Ca2+ dynamics. This conceptual outline is intended to inform and guide future research, underpinning novel therapeutic avenues for retinal-associated disorders. [ABSTRACT FROM AUTHOR]

Unraveling the neuronal mechanisms of fear learning might allow neuroscientists to make links between a learned behavior and the underlying plasticity at specific synaptic connections. In fear learning, an innocuous sensory event such as a tone (called the conditioned stimulus, CS) acquires an emotional value when paired with an aversive outcome (unconditioned stimulus, US). Here, we review earlier studies that have shown that synaptic plasticity at thalamic and cortical afferents to the lateral amygdala (LA) is critical for the formation of auditory-cued fear memories. Despite the early progress, it has remained unclear whether there are separate synaptic inputs that carry US information to the LA to act as a teaching signal for plasticity at CS-coding synapses. Recent findings have begun to fill this gap by showing, first, that thalamic and cortical auditory afferents can also carry US information; second, that the release of neuromodulators contributes to US-driven teaching signals; and third, that synaptic plasticity additionally happens at connections up- and downstream of the LA. Together, a picture emerges in which coordinated synaptic plasticity in serial and parallel circuits enables the formation of a finely regulated fear memory. [ABSTRACT FROM AUTHOR]

Background: SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. Methods: We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. Results: We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. Limitations: Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. Conclusions: Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that have been implicated in a plethora of neuronal processes. Nevertheless, their role in regulating brain activity in the context of sleep has so far received little attention. To test their involvement, we deleted mature miRNAs in post-mitotic neurons at two developmental ages, i.e., in early adulthood using conditional Dicer knockout (cKO) mice and in adult mice using an inducible conditional Dicer cKO (icKO) line. In both models, electroencephalographic (EEG) activity was affected and the response to sleep deprivation (SD) altered; while the rapid-eye- movement sleep (REMS) rebound was compromised in both, the increase in EEG delta (1 to 4 Hz) power during non-REMS (NREMS) was smaller in cKO mice and larger in icKO mice compared to controls. We subsequently investigated the effects of SD on the forebrain miRNA transcriptome and found that the expression of 48 miRNAs was affected, and in particular that of the activity-dependent miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75 to 1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates genes involved in glutamatergic neurotransmission. A subset of these genes was also affected in the cortices of sleep-deprived, miR-709- inhibited mice. Our data implicate miRNAs in the regulation of EEG activity and indicate that miR-709 links neuronal activity during wakefulness to brain synchrony during sleep through the regulation of glutamatergic signaling. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) promotes neocortical output to the thalamus and brainstem by preferentially enhancing the postsynaptic excitability of layer 5 pyramidal tract (PT) neurons relative to neighboring intratelencephalic (IT) neurons. Less is known about how ACh regulates the excitatory synaptic drive of IT and PT neurons. To address this question, spontaneous excitatory postsynaptic potentials (sEPSPs) were recorded in dual recordings of IT and PT neurons in slices of prelimbic cortex from adult female and male mice. ACh (20 µM) enhanced sEPSP amplitudes, frequencies, rise-times, and half-widths preferentially in PT neurons. These effects were blocked by the muscarinic receptor antagonist atropine (1 µM). When challenged with pirenzepine (1 µM), an antagonist selective for M1-type muscarinic receptors, ACh instead reduced sEPSP frequencies, suggesting that ACh may generally suppress synaptic transmission in the cortex via non-M1 receptors. Cholinergic enhancement of sEPSPs in PT neurons was not sensitive to antagonism of GABA receptors with gabazine (10 µM) and CGP52432 (2.5 µM) but was blocked by tetrodotoxin (1 µM), suggesting that ACh enhances action-potential-dependent excitatory synaptic transmission in PT neurons. ACh also preferentially promoted the occurrence of synchronous sEPSPs in dual recordings of PT neurons relative to IT-PT and IT-IT parings. Finally, selective chemogenetic silencing of hM4Di-expressing PT, but not commissural IT, neurons blocked cholinergic enhancement of sEPSP amplitudes and frequencies in PT neurons. These data suggest that, in addition to selectively enhancing the postsynaptic excitability of PT neurons, M1 receptor activation promotes corticofugal output by amplifying recurrent excitation within networks of PT neurons. [ABSTRACT FROM AUTHOR]

Synaptic transmission plays an important and time-sensitive role in the nervous system. Although the amplitude of neurotransmission is positively related to the intensity of external stimulus, whether stronger stimulus could trigger synaptic transmission faster remains unsolved. Our present work in the primary sensory system shows that besides the known effect of larger amplitude, stronger stimulus triggers the synaptic transmission faster, which is regulated by the earlier started action potential (AP), independent of the AP's amplitude. More importantly, this model is further extended from the sensory system to the hippocampus, implying broad applicability in the nervous system. Together, we found that stronger stimulus induces AP faster, which suggests to trigger the neurotransmission faster, implying that the occurrence time of neurotransmission, as well as the amplitude, plays an important role in the timely and effective response of nervous system. [ABSTRACT FROM AUTHOR]

O-GlcNAcylation is a posttranslational modification where N-acetylglucosamine (O-GlcNAc) is attached and detached from a serine/threonine position by two enzymes: O-GlcNAc transferase and O-GlcNAcase. In addition to roles in diabetes and cancer, recent pharmacological and genetic studies have revealed that O-GlcNAcylation is involved in neuronal function, specifically synaptic transmission. Global alteration of the O-GlcNAc level does not affect basal synaptic transmission while the effect on synaptic plasticity is unclear. Although synaptic proteins that are O-GlcNAcylated are gradually being discovered, the mechanism of how O-GlcNAcylated synaptic protein modulate synaptic transmission has only been reported on CREB, synapsin, and GluA2 subunit of AMPAR. Future research enabling the manipulation of O-GlcNAcylation in individual synaptic proteins should reveal hidden aspects of O-GlcNAcylated synaptic proteins as modulators of synaptic transmission. [ABSTRACT FROM AUTHOR]