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Insulator materials can trap charges, referring to electrets, which are attractive for transistors and memories. However, insulators intrinsically exhibit high electrical resistance, thus the charge injection and release inside insulators typically need high voltage or long bias time, limiting the applications that require high writing/erasing speed. In this work, insulator polymer polystyrene (PS) film is treated by a soft plasma, which selectively induces a high density of charge traps at the top surface, without changing the electronic properties of the underneath materials. The thus‐prepared surface is easily occupied by external neat charges to form a meso‐stable electret. Subsequently, the electret is used as an ultra‐thin charge trapping layer to build transistors for some applications. Consequently, in transistor architecture, the charge injection and release at soft plasma treated PS surface can be more easily achieved in a short stimulus as compared with pristine PS counterpart, and the density of captured holes under gate bias reaches 2.9 × 1012 cm−2 in 1 ms. Under UV irradiation, charge transfer occurs from the photo‐excited semiconductor to the electret, contributing to the rapid release of the stored holes. This soft plasma‐generated electret is then utilized for flash‐type memories, photodetectors, and artificial synapses. [ABSTRACT FROM AUTHOR]

Nervous system of Periplaneta americana cockroach is used in a wide range of pharmacological studies, including electrophysiological techniques. This paper presents its role as a preparation in the development of toxinological studies in the following electrophysiological methods: double-oil-gap technique on isolated giant axon, patch-clamp on DUM (dorsal unpaired median) neurons, microelectrode technique in situ conditions on axon in connective and DUM neurons in ganglion, and single-fiber oil-gap technique on last abdominal ganglion synapse. At the end the application of cockroach synaptosomal preparation is mentioned. [ABSTRACT FROM AUTHOR]

Metal neurotoxicity is a global health concern. This paper summarizes the evidence for metal interactions with synaptic transmission and synaptic plasticity. Presynaptically metal ions modulate neurotransmitter release through their interaction with synaptic vesicles, ion channels, and the metabolism of neurotransmitters (NT). Many metals (e.g., Pb2+, Cd2+, and Hg+) also interact with intracellular signaling pathways. Postsynaptically, processes associated with the binding of NT to their receptors, activation of channels, and degradation of NT are altered by metals. Zn2+, Pb2+, Cu2+, Cd2+, Ni2+, Co2+, Li3+, Hg+, and methylmercury modulate NMDA, AMPA/kainate, and/or GABA receptors activity. Al3+, Pb2+, Cd2+, and As2O3 also impair synaptic plasticity by targeting molecules such as CaM, PKC, and NOS as well as the transcription machinery involved in the maintenance of synaptic plasticity. The multiple effects of metals might occur simultaneously and are based on the specific metal species, metal concentrations, and the types of neurons involved. [ABSTRACT FROM AUTHOR]

Background and purpose: Synaptic deficiency is generally accepted to be involved in major depression, and accordingly classic antidepressants exert their effects through enhancing synaptic efficiency. Hypericin is one of the major active constituents of extracts of St. John's Wort ( Hypericum perforatum L.) with antidepressive actions, but little is known about its therapeutic mechanisms. Our aim was to explore whether hypericin has a modulatory effect on neuronal action potential (AP) duration by acting on voltage-gated ion channels. Experimental approach: We used voltage-clamp and current-clamp techniques in a whole-cell configuration to study primary cultures of neonatal rat hippocampal neurones. We measured the effects of extracellularly applied hypericin on AP duration as well as on voltage-gated Na+, IA and IK currents. Key results: Extracellularly applied hypericin dose-dependently increased AP duration but barely affected its amplitude. Further analysis revealed that hypericin inhibited both transient IA and delayed rectifier IK potassium currents. In contrast, hypericin exerted no significant effect on both Na+ peak current and its decay kinetics. Conclusions and implications: Extracellularly applied hypericin increased AP duration, which might be ascribed to its effect on IA and IK currents. As a small increase in AP duration could lead to a dramatic increase in synaptic efficiency, our results imply that hypericin might exert its antidepressant effects by enhancing presynaptic efficiency. [ABSTRACT FROM AUTHOR]

Background and Purpose: N-methyl-D-aspartate (NMDA) receptors represent an attractive drug target for the treatment of neurological and neurodegenerative disorders associated with glutamate-induced excitotoxicity. The aim of this study was to map the binding domain of high affinity 5-substituted benzimidazole derivatives [N-{2-[(4-benzylpiperidin-1-yl)methyl]benzimidazol-5-yl}methanesulphonamide (XK1) and N-[2-(4-phenoxybenzyl)benzimidazol-5-yl]methanesulphonamide (XK2)] on the GluN2B subunit of the NMDA receptor.Experimental Approach: The pharmacological antagonistic profiles of XK1 and XK2 were assessed using in vitro rat primary cerebrocortical neurones and two-electrode voltage clamp on Xenopus oocytes expressing heterologous GluN1/GluN2B receptors. Direct ligand binding was determined using the recombinant amino-terminal domain (ATD) of GluN2B.Key Results: XK1 and XK2 effectively protected against NMDA-induced excitotoxicity in rat primary cortical neurones. Low concentrations of XK1 (10 nM) and XK2 (1 nM) significantly reversed neuronal death. Both compounds failed to inhibit currents measured from oocytes heterologously expressing GluN1-1a subunit co-assembled with the ATD-deleted GluN2B subunit. XK1 and XK2 showed specific binding to recombinant protein of GluN2B ATD with low nanomolar affinities. Several residues in the recombinant ATD of GluN2B were identified to be critical for conferring XK1 and XK2 sensitivity. The inhibitory effects of XK1 and XK2 were pH-sensitive, being increased at acidic pH.Conclusions and Implications: These results demonstrate that XK1 and XK2 are effective neuroprotective agents in vitro and indicate that 5-substituted benzimidazole derivatives inhibit GluN1/GluN2B receptors via direct binding to the ATD of the GluN2B subunit. These compounds represent valuable alternatives to the classical antagonist ifenprodil as pharmacological tools for studying GluN2B-containing NMDA receptors. [ABSTRACT FROM AUTHOR]

This paper analyzes a system in which two Morris–Lecar neuron models are mutually coupled through an electrical synapse (gap junction) and a chemical synapse (α function), and sinusoidal external forces with different periods are applied to the individual neurons. This model is a dynamical system which has been proposed in order to account for the synchronization between neurons based on the circadian clock rhythm. In fact, both mutual synchronization and synchronization to a periodic external force are observed in the rhythm of the average firing rate (sustained temporal behavior of firing/nonfiring response). By an analysis of bifurcation phenomena observed in the system, the generation mechanism for synchronization/desynchronization, as reported in physiological experiments, can be accounted for. © 2005 Wiley Periodicals, Inc. Syst Comp Jpn, 36(8): 1–14, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/scj.20348 [ABSTRACT FROM AUTHOR]

The synchronization of populations of interacting spiking neurons is a topic of interest for understanding the operation of the brain and for developing oscillatory‐based biomimetic computation. The analysis of the operation of neurons by models such as Hodgkin–Huxley (HH) and FitzHugh–Nagumo (FHN) is based on the electrical and electrochemical concepts. The application of small‐signal AC impedance and equivalent circuit methods is a promising tool for the fabrication of artificial neurons and synapses with memristor technologies for neuromorphic computation and sensory‐motor autonomous systems. The time domain and impedance spectroscopy analysis of two FHN neurons coupled with a time delay related to the propagation of the action potentials is developed. Depending on the coupling strength and delay time constant, the two neurons become synchronized, in phase opposition for a weak coupling, and in alternating spike packets for the strong interaction. The delayed interaction introduces a new element in the equivalent circuit. A new oscillatory impedance that causes curling of the basic spectral patterns associated with the onset of a limit cycle in the presence of Hopf bifurcations is found. The new pattern is appealing as an experimental tool to determine experimentally the extent of coupling between neurons. [ABSTRACT FROM AUTHOR]

Synaptic polarity, that is, whether synapses are inhibitory (−) or excitatory (+), is challenging to map, despite being a key to understand brain function. Here, synaptic polarity is inferred computationally considering three experimental scenarios, depending on the nature of available input data, using the Caenorhabditis elegans connectome as an example. First, the inputs consist of detailed neurotransmitter (NT) and receptor (R) gene expression, integrated through the connectome model (CM). The CM formulates the problem through a wiring rule network that summarizes how NT‐R pairs govern synaptic polarity, and resolves 356 synaptic polarities in addition to the 1752 known polarities. Second, known synaptic polarities are considered as an input, in addition to the NT and R gene expression data, but without wiring rules. These data train the spatial connectome model, which infers the polarity of 81% of the CM‐resolved connections at >95$>95$% precision, while also inferring 147 of the remaining unknown polarities. Last, without known expression or wiring rules, polarities are inferred through a network sign prediction problem. As an illustration of high performance in this case, the generalized CM is introduced. These results address imminent challenges in unveiling large‐scale synaptic polarities, an essential step toward more realistic brain models. [ABSTRACT FROM AUTHOR]

The descending auditory system modulates the ascending system at every level. The final descending, or efferent, stage comprises lateral olivocochlear and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC‐mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB–MOC synapses exhibit short‐term depression, suggesting reduced MNTB–MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound‐evoked activity in MNTB neurons in vivo, MNTB–MOC synapses may be tonically depressed. To probe this, we characterized short‐term plasticity of MNTB–MOC synapses in mouse brain slices. We mimicked in vivo‐like temperature and extracellular calcium conditions, and in vivo‐like activity patterns of fast synaptic activation rates, sustained activation and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, postsynaptic currents in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression. Key points: Inhibitory synapses from the medial nucleus of the trapezoid body (MNTB) onto medial olivocochlear (MOC) neurons exhibit short‐term plasticity that is sensitive to calcium and temperature, with enhanced synaptic depression occurring at higher calcium concentrations and at room temperature.High rates of background synaptic activity that mimic the upper limits of spontaneous MNTB activity cause tonic synaptic depression of MNTB–MOC synapses that limits further synaptic inhibition.High rates of activity at MNTB–MOC synapses cause synaptic summation with concurrent depression to yield a response with an initial large amplitude that decays to a tonic inhibition. [ABSTRACT FROM AUTHOR]

The field of connectomics aims to reconstruct the wiring diagram of Neurons and synapses to enable new insights into the workings of the brain. Reconstructing and analyzing the Neuronal connectivity, however, relies on many individual steps, starting from high‐resolution data acquisition to automated segmentation, proofreading, interactive data exploration, and circuit analysis. All of these steps have to handle large and complex datasets and rely on or benefit from integrated visualization methods. In this state‐of‐the‐art report, we describe visualization methods that can be applied throughout the connectomics pipeline, from data acquisition to circuit analysis. We first define the different steps of the pipeline and focus on how visualization is currently integrated into these steps. We also survey open science initiatives in connectomics, including usable open‐source tools and publicly available datasets. Finally, we discuss open challenges and possible future directions of this exciting research field. [ABSTRACT FROM AUTHOR]

Patients suffering from anorexia nervosa (AN) display altered neural activity, morphological, and functional connectivity in the fronto‐striatal circuit. In addition, hypoglutamatergic transmission and aberrant excitability of the medial prefrontal cortex (mPFC) observed in AN patients might underpin cognitive deficits that fuel the vicious cycle of dieting behavior. To provide a molecular mechanism, we employed the activity‐based anorexia (ABA) rat model, which combines the two hallmarks of AN (i.e., caloric restriction and intense physical exercise), to evaluate structural remodeling together with alterations in the glutamatergic signaling in the mPFC and their impact on temporal memory, as measured by the temporal order object recognition (TOOR) test. Our data indicate that the combination of caloric restriction and intense physical exercise altered the homeostasis of the glutamate synapse and reduced spine density in the mPFC. These events, paralleled by an impairment in recency discrimination in the TOOR test, are associated with the ABA endophenotype. Of note, after a 7‐day recovery period, body weight was recovered and the mPFC structure normalized but ABA rats still exhibited reduced post‐synaptic stability of AMPA and NMDA glutamate receptors associated with cognitive dysfunction. Taken together, these data suggest that the combination of reduced food intake and hyperactivity affects the homeostasis of the excitatory synapse in the mPFC contributing to maintain the aberrant behaviors observed in AN patients. Our findings, by identifying novel potential targets of AN, may contribute to more effectively direct the therapeutic interventions to ameliorate, at least, the cognitive effects of this psychopathology. [ABSTRACT FROM AUTHOR]

Stressful experiences evoke, among others, a rapid increase in brain (nor)epinephrine (NE) levels and a slower increase in glucocorticoid hormones (GCs) in the brain. Microglia are key regulators of neuronal function and contain receptors for NE and GCs. These brain cells may therefore potentially be involved in modulating stress effects on neuronal function and learning and memory. In this review, we discuss that stress induces (1) an increase in microglial numbers as well as (2) a shift toward a pro‐inflammatory profile. These microglia have (3) impaired crosstalk with neurons and (4) disrupted glutamate signaling. Moreover, microglial immune responses after stress (5) alter the kynurenine pathway through metabolites that impair glutamatergic transmission. All these effects could be involved in the impairments in memory and in synaptic plasticity caused by (prolonged) stress, implicating microglia as a potential novel target in stress‐related memory impairments. [ABSTRACT FROM AUTHOR]

Presents abstracts of papers featured in the "Journal of Neurochemistry" that deal with cytoskeleton, intercellular transport, vesicle traffic and synaptic function. "Co-localization of the P2Y1 ADP receptor and the NTPDase 1/CD39 in caveolae"; "Splicing variants of human norepinephrine transporter that regulate the functional expression".

Provides information on a study which examined the role of ubiquitin pathway proteins in the regulation of synaptic development. Opposing roles of Highwire and Fat facets in presynaptic development at the Drosophila neuromuscular junction; Information on the ubiquitinated substrates of Highwire and Fat facets in presynaptic neurons; Conclusions.

Microglial cells are the scions of foetal macrophages which invade the neural tube early during embryogenesis. The nervous tissue environment instigates the phenotypic metamorphosis of foetal macrophages into idiosyncratic surveilling microglia, which are generally characterised by a small cell body and highly ramified motile processes that constantly scan the nervous tissue for signs of changes in homeostasis and allow microglia to perform crucial homeostatic functions. The surveilling microglial phenotype is evolutionarily conserved from early invertebrates to humans. Despite this evolutionary conservation, microglia show substantial heterogeneity in their gene and protein expression, as well as morphological appearance. These differences are age, region and context specific and reflect a high degree of plasticity underlying the life‐long adaptation of microglia, supporting the exceptional adaptive capacity of the central nervous system. Microgliocytes are essential elements of cellular network formation and refinement in the developing nervous tissue. Several distinct patrolling modes of microglial processes contribute to the formation, modification, and pruning of synapses; to the support and protection of neurones through microglial–somatic junctions; and to the control of neuronal and axonal excitability by specific microglia–axonal contacts. In pathology, microglia undergo proliferation and reactive remodelling known as microgliosis, which is context dependent, yet represents an evolutionarily conserved defence response. Microgliosis results in the emergence of multiple disease and context‐specific reactive states; in addition, neuropathology is associated with the appearance of specific protective or recovery microglial forms. In summary, the plasticity of microglia supports the development and functional activity of healthy nervous tissue and provides highly sophisticated defences against disease. [ABSTRACT FROM AUTHOR]

Organic memristive devices are promising elements to be used in memory tasks, neuromorphic systems, and bioelectronics as hardware analogs of synapses. Among other materials, small molecules are considered in this field as candidates with more adjustable properties and fine chemical structures. Herein, the first organic memristive device based on benzothieno[3,2‐b][1]‐benzothiophene (BTBT) siloxane dimer is reported. The device resistance programming by voltage pulses with various control parameters is demonstrated: amplitude, frequency, and pulse duty cycle. It is proved that the device has at least four different resistive states in each case. In addition, the device shows 2.5 × 104 cycles of sustainable operation in the endurance test with ROFF/RON ratio exceeding 5. [ABSTRACT FROM AUTHOR]

The retina has the highest relative energy consumption of any tissue, depending on a steady supply of glucose from the bloodstream. Glucose uptake is mediated by specific transporters whose regulation and expression are critical for the pathogenesis of many diseases, including diabetes and diabetic retinopathy. Here, we used immunofluorescence to show that glucose transporter‐2 (GLUT2) is expressed in horizontal cells of the mouse neuroretina in proximity to inner retinal capillaries. To study the function of GLUT2 in the murine retina, we used organotypic retinal explants, cultivated under entirely controlled, serum‐free conditions and exposed them to streptozotocin, a cytotoxic drug transported exclusively by GLUT2. Contrary to our expectations, streptozotocin did not measurably affect horizontal cell viability, while it ablated rod and cone photoreceptors in a concentration‐dependent manner. Staining for poly‐ADP‐ribose (PAR) indicated that the detrimental effect of streptozotocin on photoreceptors may be associated with DNA damage. The negative effect of streptozotocin on the viability of rod photoreceptors was counteracted by co‐administration of either the inhibitor of connexin‐formed hemi‐channels meclofenamic acid or the blocker of clathrin‐mediated endocytosis dynasore. Remarkably, cone photoreceptors were not protected from streptozotocin‐induced degeneration by neither of the two drugs. Overall, these data suggest the existence of a GLUT2‐dependent glucose transport shuttle, from horizontal cells into photoreceptor synapses. Moreover, our study points at different glucose uptake mechanisms in rod and cone photoreceptors. [ABSTRACT FROM AUTHOR]

SNCA protein product, α‐synuclein, is widely renowned for its role in synaptogenesis and implication in both aging and Parkinson's disease (PD), but research efforts are still needed to elucidate its physiological functions and mechanisms of regulation. In this work, we aim to characterize SNCA‐AS1, antisense transcript to the SNCA gene, and its implications in cellular processes. The overexpression of SNCA‐AS1 upregulates both SNCA and α‐synuclein and, through RNA‐sequencing analysis, we investigated the transcriptomic changes of which both genes are responsible. We highlight how they impact neurites' extension and synapses' biology, through specific molecular signatures. We report a reduced expression of markers associated with synaptic plasticity, and we specifically focus on GABAergic and dopaminergic synapses, for their relevance in aging processes and PD, respectively. A reduction in SNCA‐AS1 expression leads to the opposite effect. As part of this signature is co‐regulated by the two genes, we discriminate between functions elicited by genes specifically altered by SNCA‐AS1 or SNCA's overexpression, observing a relevant role for SNCA‐AS1 in synaptogenesis through a shared molecular signature with SNCA. We also highlight how numerous deregulated pathways are implicated in aging‐related processes, suggesting that SNCA‐AS1 could be a key player in cellular senescence, with implications for aging‐related diseases. Indeed, the upregulation of SNCA‐AS1 leads to alterations in numerous PD‐specific genes, with an impact highly comparable to that of SNCA's upregulation. Our results show that SNCA‐AS1 elicits its cellular functions through the regulation of SNCA, with a specific modulation of synaptogenesis and senescence, presenting implications in PD. [ABSTRACT FROM AUTHOR]

Neuromorphic in‐memory computing systems, comprising artificial synapses and neurons, can overcome the energy inefficiency and throughput limitation of today's von Neumann computing architecture. Recently, powered by the unique properties of quantum materials, for example, high mobility, outstanding sensitivity, and strong quantum effect, researchers have built quantum artificial synapses to mimic the biological ones. These quantum electronic/photonic synapses can precisely define their conductance state (or synaptic weight) for emulating synaptic behaviors, which shows bionic performance unreachable by other conventional materials. In this review, the significant achievements in quantum artificial synapses are summarized. First, potential quantum materials used in artificial synapses are discussed with particular attention to quantum dots, nanowires, layered materials, and quasi‐2DEG interfaces. Then, the major quantum effects that are utilized in quantum artificial synapses, for example, Josephson effect, quantum tunneling, and spin memory, are reviewed. In addition to the discussion on a single synaptic device, the macroscale integration into artificial visual systems and artificial nerve networks are also highlighted. Finally, the associated future research trends and target applications are also discussed. [ABSTRACT FROM AUTHOR]

Ca2+/calmodulin‐dependent protein kinase II (CaMKII) is known to be a crucial regulator in the post‐synapse during long‐term potentiation. This important protein has been the subject of many studies centered on understanding memory at the molecular, cellular, and organismic level. CaMKII is encoded by four genes in humans, all of which undergo alternative splicing at the RNA level, leading to an enormous diversity of expressed proteins. Advances in sequencing technologies have facilitated the discovery of many new CaMKII transcripts. To date, newly discovered CaMKII transcripts have been incorporated into an ambiguous naming scheme. Herein, we review the initial experiments leading to the discovery of CaMKII and its subsequent variants. We propose the adoption of a new, unambiguous naming scheme for CaMKII variants. Finally, we discuss biological implications for CaMKII splice variants. [ABSTRACT FROM AUTHOR]

The human brain, with high energy-efficient and parallel processing ability, inspires to mitigate power issues perplexing von Neumann architecture. As one of the essential components constructing the human brain, the emulation of biological synapses exploiting electronic devices consuming power at a biological level lays the foundation for the implementation of energy-efficient neuromorphic computing. Besides, signal matching between biologically-related stimuli and the driving voltage of artificial synapses helps to realize intelligent neuromorphic interfaces and sustainable energy. Here, ultra-sensitive artificial synapse stimulated at 1 mV with energy consumption of 132 attojoule/synaptic event is demonstrated. Biological signal matching and low power application are realized simultaneously based on sodium acetate (NaAc) doped polyvinyl alcohol (PVA) electrolyte. The biphasic current, which comprises the electrical-and ion-mediation current component, contributes to enrich synaptic functions compared to monophasic synaptic behavior. Moreover, freestanding NaAc-doped PVA membrane functions as both dielectric layer and mechanical support and facilitates to achieve flexible, transferable artificial synapse, which maintains functional stability at an ultralow voltage and power even after bending tests. Thus, encompassing superior sensitivity, low energy, and multiple functionalities with flexible, self-supported, biocompatible property, takes a step to construct energetically-efficient, complex neuromorphic systems for wearable, implantable medicines as well as smart bio-electronic interfaces. [ABSTRACT FROM AUTHOR]

In the learning of a neural network model, the excitatory and inhibitory synapses and the threshold are modified. There is little discussion, however, as to what function the neural model can realize in the pattern separation when the synapses or the threshold is modifiable. This paper considers the analog-threshold neuron model, and discusses the pattern separation performance of the neuron when excitatory synapse, inhibitory synapse and threshold are modifiable. As a result of the discussion, it is shown that the pattern-separating function of the neuron is maximized when the excitatory and inhibitory synapses as well as the threshold are modifiable. Then a learning system is proposed where the excitatory and inhibitory synapses as well as the threshold are simultaneously modifiable. A model with the proposed learning scheme is analyzed. Finally, it is shown by computer simulation that the proposed model operates as the analysis predicts. [ABSTRACT FROM AUTHOR]

A neural network model which learns to discriminate spatio-temporal patterns is proposed. The model is composed of pulse-type neuron models taking account of its realization with hardware. Input pulse trains whose dynamic features are emphasized by ON-type neurons propagate through the uniform neural chains and are then fed to plastic neuron models which are laterally interconnected with suitable inhibitory/excitatory weights. After iterative training steps, various phases of input spatio-temporal patterns are reproduced on the spatial patterns of synaptic weights, and plastic neurons are organized to form some functional groups that respond only to some voice features. [ABSTRACT FROM AUTHOR]

Assesses studies which examined the notion that memories depend on persistent changes in transmission of synapses in the hippocampus. Mechanisms for an increased number of terminals releasing transmitter; Evidence verifying the phenomenon of long-term potentiation (LTP) of synaptic transmission; Approach used to discriminate between pre- and post-synaptic sites for LTP expression.

Proteasome activity at the excitatory synapse plays an important role in neuronal communication. The proteasome translocation to synapses is mediated by neuronal activity, in particular the activation of N‐methyl‐d‐aspartate receptors (NMDARs). These receptors are composed of different subunits with distinct trafficking properties that provide various signalling and plasticity features to the synapse. Yet whether the interplay between the proteasome and NMDAR relies on specific subunit properties remain unclear. Using a combination of single molecule and immunocytochemistry imaging approaches in rat hippocampal neurons, we unveil a specific interplay between GluN2B‐containing NMDARs (GluN2B‐NMDARs) and the synaptic proteasome. Sustained proteasome activation specifically increases GluN2B‐NMDAR (not GluN2A‐NMDAR) lateral diffusion. In addition, when GluN2B‐NMDAR expression is downregulated, the proteasome localization decreases at glutamatergic synapses. Collectively, our data fuel a model in which the cellular dynamics and location of GluN2B‐NMDARs and proteasome are intermingled, shedding new lights on the NMDAR‐dependent regulation of synaptic adaptation. [ABSTRACT FROM AUTHOR]

Although calyx of Held synapses undergo dramatic changes around the hearing onset, previous in vivo studies suggest that the calyx synapses undergo further post‐hearing maturation process. While developmental changes over the hearing onset have been extensively studied, this post‐hearing maturation process remained relatively little investigated. Because of post‐hearing maturation, previous results from studies around hearing onset and studies of post‐hearing calyx synapses are somewhat inconsistent. Here, we characterized the post‐hearing maturation of calyx synapses with regard to in vitro electrophysiological properties in rats and mice. We found that parameters for residual glutamate in the cleft during a train, EPSC kinetics, and vesicle pool size became close to a full mature level by P14, but they further matured until P16 in the rats. Consistently, the phasic and slow EPSCs evoked by action potential trains at P16 calyx synapses were not different from those at P18 or P25 under physiological extracellular [Ca2+]o (1.2 mM). In contrast, the parameters for residual current and EPSC kinetics displayed drastic changes until P16 in mice, and slow EPSCs during the train further decreased between P16 and P18, suggesting that maturation of calyx synapses progresses at least up to P16 in rats and P18 in mice. [ABSTRACT FROM AUTHOR]

The nonlinear spiking neural P systems (NSNP systems) are new types of computation models, in which the state of neurons is represented by real numbers, and nonlinear spiking rules handle the neuron's firing. In this work, in order to improve computing performance, the weights and delays are introduced to the NSNP system, and universal nonlinear spiking neural P systems with delays and weights on synapses (NSNP-DW) are proposed. Weights are treated as multiplicative constants by which the number of spikes is increased when transiting across synapses, and delays take into account the speed at which the synapses between neurons transmit information. As a distributed parallel computing model, the Turing universality of the NSNP-DW system as number generating and accepting devices is proven. 47 and 43 neurons are sufficient for constructing two small universal NSNP-DW systems. The NSNP-DW system solving the Subset Sum problem is also presented in this work. [ABSTRACT FROM AUTHOR]

Olfactory receptor neurons (ORNs) of the hawkmoth Manduca sexta sensitize via cAMP‐ and adapt via cGMP‐dependent mechanisms. Perforated patch clamp recordings distinguished 11 currents in these ORNs. Derivatives of cAMP and/or cGMP antagonistically affected three of five K+ currents and two non‐specific cation currents. The Ca2+‐dependent K+ current IK(Ca2+) and the sensitive pheromone‐dependent K+ current IK(cGMP−), which both express fast kinetics, were inhibited by 8bcGMP, while a slow K+ current, IK(cGMP+), was activated by 8bcGMP. Furthermore, application of 8bcAMP blocked slowly activating, zero mV‐reversing, non‐specific cation currents, ILL and Icat(PKC?), which remained activated in the presence of 8bcGMP. Their activations pull the membrane potential towards their 0‐mV reversal potentials, in addition to increasing intracellular Ca2+ levels voltage‐ and ILL‐dependently. Twenty minutes after application, 8bcGMP blocked a TEA‐independent K+ current, IK(noTEA), and a fast cation current, Icat(nRP), which both shift the membrane potential to negative values. We conclude that conditions of sensitization are maintained at high levels of cAMP, via specific opening/closure of ion channels that allow for fast kinetics, hyperpolarized membrane potentials, and low intracellular Ca2+ levels. In contrast, adaptation is supported via cGMP, which antagonizes cAMP, opening Ca2+‐permeable channels with slow kinetics that stabilize depolarized resting potentials. The antagonistic modulation of peripheral sensory neurons by cAMP or cGMP is reminiscent of pull–push mechanisms of neuromodulation at central synapses underlying metaplasticity. [ABSTRACT FROM AUTHOR]

Key points: The present study aimed to determine the sensory adaptation characteristics of hair cell ribbon synapses in vivo.Hair cells of the zebrafish lateral line transmit hydrodynamic stimuli to the posterior lateral line ganglion afferent neurons.Excitatory hair bundle deflections by water‐jet stimuli cause glutamate release at hair cell synapses with a rapid (phasic) and a sustained component, which are likely linked to the exocytosis of distinct vesicle pools.The glutamate‐induced increase in afferent neuron firing rate adapts over time, which is mirrored by the depression of neurotransmitter release, without preventing phase‐locking.Adaptation also occurs during inhibitory hair bundle displacements, highlighting a shift in the sensitivity range of the lateral line during prolonged stimulation.Postsynaptic mechanisms exert some degree of regulation on the afferent firing adaptation.We conclude that vesicle depletion is the primary determinant of firing rate adaptation, allowing lateral line hair cell ribbon synapses to maintain sensitivity to sustained stimuli. Adaptation is used by sensory systems to adjust continuously their sensitivity to match changes in environmental stimuli. In the auditory and vestibular systems, the release properties of glutamate‐containing vesicles at the hair cell ribbon synapses play a crucial role in sensory adaptation, thus shaping the neural response to sustained stimulation. How ribbon synapses regulate the release of glutamate and how they modulate afferent responses in vivo is still largely unknown. Here, we have used two‐photon imaging and electrophysiology to investigate the synaptic transfer characteristics of the hair cells in the context of sensory adaptation in live zebrafish. Prolonged and repeated water‐jet stimulation of the hair cell stereociliary bundles caused adaptation of the action potential firing rate elicited in the afferent neurons. By monitoring glutamate at ribbon synapses using time‐lapse imaging, we identified two kinetically distinct release components: a rapid response that was exhausted within 50–100 ms and a slower and sustained response lasting the entire stimulation. After repeated stimulations, the recovery of the fast component followed a biphasic time course. Depression of glutamate release was largely responsible for the rapid firing rate adaptation recorded in the afferent neurons. However, postsynaptic Ca2+ responses had a slower recovery time course compared to that of glutamate release, indicating that they are likely to contribute to the afferent firing adaptation. Hair cells also exhibited a form of adaptation during inhibitory bundle stimulations. We conclude that hair cells have optimised their synaptic machinery to encode prolonged stimuli and to maintain their sensitivity to new incoming stimuli. Key points: The present study aimed to determine the sensory adaptation characteristics of hair cell ribbon synapses in vivo.Hair cells of the zebrafish lateral line transmit hydrodynamic stimuli to the posterior lateral line ganglion afferent neurons.Excitatory hair bundle deflections by water‐jet stimuli cause glutamate release at hair cell synapses with a rapid (phasic) and a sustained component, which are likely linked to the exocytosis of distinct vesicle pools.The glutamate‐induced increase in afferent neuron firing rate adapts over time, which is mirrored by the depression of neurotransmitter release, without preventing phase‐locking.Adaptation also occurs during inhibitory hair bundle displacements, highlighting a shift in the sensitivity range of the lateral line during prolonged stimulation.Postsynaptic mechanisms exert some degree of regulation on the afferent firing adaptation.We conclude that vesicle depletion is the primary determinant of firing rate adaptation, allowing lateral line hair cell ribbon synapses to maintain sensitivity to sustained stimuli. [ABSTRACT FROM AUTHOR]

Severe voluntary food restriction is the defining symptom of anorexia nervosa (AN), but anxiety and excessive exercise are maladaptive symptoms that contribute significantly to the severity of AN and which individuals with AN have difficulty suppressing. We hypothesized that the excitability of hippocampal pyramidal neurons, known to contribute to anxiety, leads to the maladaptive behavior of excessive exercise. Conversely, since glutamate transporter GLT‐1 dampens the excitability of hippocampal pyramidal neurons through the uptake of ambient glutamate and suppression of the GluN2B‐subunit containing NMDA receptors (GluN2B‐NMDARs), GLT‐1 may contribute toward dampening excessive exercise. This hypothesis was tested using the mouse model of AN, called activity‐based anorexia (ABA), whereby food restriction evokes the maladaptive behavior of excessive wheel running (food restriction‐evoked running, FRER). We tested whether individual differences in ABA vulnerability of mice, quantified based on FRER, correlated with individual differences in the levels of GLT‐1 at excitatory synapses of the hippocampus. Electron microscopic immunocytochemistry (EM‐ICC) was used to quantify GLT‐1 levels at the excitatory synapses of the hippocampus. The FRER seen in individual mice varied more than 10‐fold, and Pearson correlation analyses revealed a strong negative correlation (p =.02) between FRER and GLT‐1 levels at the axon terminals of excitatory synapses and at the surrounding astrocytic plasma membranes. Moreover, synaptic levels of GluN2B‐NMDARs correlated strongly with GLT‐1 levels at perisynaptic astrocytic plasma membranes. There is at present no accepted pharmacotherapy for AN, and little is known about the etiology of this deadly illness. Current findings suggest that drugs increasing GLT‐1 expression may reduce AN severity through the reduction of GluN2B‐NMDAR activity. [ABSTRACT FROM AUTHOR]

Designing transparent flexible electronics with multi‐biological neuronal functions and superior flexibility is a key step to establish wearable artificial intelligence equipment. Here, a flexible ionic gel‐gated VO2 Mott transistor is developed to simulate the functions of the biological synapse. Short‐term and long‐term plasticity of the synapse are realized by the volatile electrostatic carrier accumulation and nonvolatile proton‐doping modulation, respectively. With the achievement of multi‐essential synaptic functions, an important sensory neuron, nociceptor, is perfectly simulated in our synaptic transistors with all key characteristics of threshold, relaxation, and sensitization. More importantly, this synaptic transistor exhibits high tolerance to the bending deformation, and the cycle‐to‐cycle variations of multi‐conductance states in potentiation and depression properties are maintained within 4%. This superior stability further indicates that our flexible device is suitable for neuromorphic computing. Simulation results demonstrate that high recognition accuracy of handwritten digits (>95%) can be achieved in a convolution neural network built from these synaptic transistors. The transparent and flexible Mott transistor based on electrically‐controlled VO2 metal‐insulator transition is believed to open up alternative approaches to developing highly stable synapses for future flexible neuromorphic systems. [ABSTRACT FROM AUTHOR]

Collybistin (CB) is a guanine nucleotide exchange factor (GEF) selectively localized at GABAergic and glycinergic postsynapses. Analysis of mRNA shows that several isoforms of collybistin are expressed in the brain. Some of the isoforms have a SH3 domain (CBSH3+) and some have no SH3 domain (CBSH3−). The CBSH3+ mRNAs are predominantly expressed over CBSH3−. However, in an immunoblot study of mouse brain homogenates, only CBSH3+ protein isoforms were detected, proposing that CBSH3− protein might not be expressed in the brain. The expression or lack of expression of CBSH3− protein is an important issue because CBSH3− has a strong effect in promoting the postsynaptic clustering of gephyrin and GABA‐A receptors (GABAARs). Moreover CBSH3− is constitutively active; therefore lower expression of CBSH3− protein might play a relatively stronger functional role than the more abundant but self‐inhibited CBSH3+ isoforms, which need to be activated. We are now showing that: (a) CBSH3− protein is expressed in the brain; (b) parvalbumin positive (PV+) interneurons show higher expression of CBSH3− protein than other neurons; (c) CBSH3− is associated with GABAergic synapses in various regions of the brain and (d) knocking down CBSH3− in hippocampal neurons decreases the synaptic clustering of gephyrin and GABAARs. The results show that CBSH3− protein is expressed in the brain and that it plays a significant role in the size regulation of the GABAergic postsynapse. [ABSTRACT FROM AUTHOR]

Summary: Memory is of central importance to the research of high‐level cognitive behaviors of humans, where the plastic synapse contributes to the memory formation. Due to the controllable conductance and high‐density integration, the memristor acts as a promising candidate of artificial synapse. In terms of memory retention time, memory contains short‐term memory (STM) and long‐term memory (LTM). Additionally, the STM can be changed to the LTM via repeated learning, and this process is called memory consolidation. A threshold‐type memristor combined with basic operational circuits is used to design a memory circuit that can emulate various memory hierarchy levels containing the STM, the LTM, and the STM‐to‐LTM transition. Threshold firing behavior can also be emulated because of the threshold characteristic of the memristor. Furthermore, a floating emulator circuit that consists of several off‐the‐shelf devices is developed to mimic the electrical behaviors of the threshold‐type memristor, and its hardware circuit implementation is presented. Finally, both simulation and experimental results validate the feasibility and effectiveness of the proposed memory circuit. [ABSTRACT FROM AUTHOR]

The revolution in genetic technology has ushered in a new age for our understanding of the underlying causes of neurodevelopmental, neuromuscular and neurodegenerative disorders, revealing that the presynaptic machinery governing synaptic vesicle fusion is compromised in many of these neurological disorders. This builds upon decades of research showing that disturbance to neurotransmitter release via toxins can cause acute neurological dysfunction. In this review, we focus on disorders of synaptic vesicle fusion caused either by toxic insult to the presynapse or alterations to genes encoding the key proteins that control and regulate fusion: the SNARE proteins (synaptobrevin, syntaxin‐1 and SNAP‐25), Munc18, Munc13, synaptotagmin, complexin, CSPα, α‐synuclein, PRRT2 and tomosyn. We discuss the roles of these proteins and the cellular and molecular mechanisms underpinning neurological deficits in these disorders. [ABSTRACT FROM AUTHOR]

Discusses a study which developed a thermodynamic model to examine the role of liposomes in the mechanism whereby nitrogen mediates the narcosis of deep diving. Details of the proton pump/leak hypothesis to account for a compromised central nervous system (CNS) or a state of unconsciousness; Impact of disordered and leaky synaptosomes on CNS; Factors that will alter the ionic gradients of synaptic vesicles in an animal model.

Inspired by the low energy consumption and highly parallel processing power of the biological neuromorphic system, the development of a brain‐inspired computing paradigm with electronic devices based artificial synapse may play an essential role in eliminating the Von Neumann bottleneck. Among candidate electronic devices, memristive devices have shown great potential for artificial synapse because of its tunable resistive switching (RS) behaviors. Herein, a biological synapse with solution‐processed MgO‐graphene oxide quantum dots (MgO‐GOQDs) based memristor is developed. The device exhibits highly controllable RS behavior owing to the enhancement of the local electric field by GOQDs and redox of GOQDs under electric fields. Moreover, essential biosynaptic functions including paired‐pulse facilitation, short‐term plasticity (STP)/long‐term plasticity (LTP), STP to LTP transition, and spike‐time‐dependent plasticity are successfully emulated. It is noteworthy that the device fabricated on a polyethylene terephthalate substrate also presents stable RS behavior after a large number of bending cycles. This study demonstrates the great potential of solution‐processed MgO–GOQD hybrid film on its application for the realization of flexible artificial neural networks. [ABSTRACT FROM AUTHOR]

Key points: Presynaptic mitochondria not only absorb but also release Ca2+ during high frequency stimulation (HFS) when presynaptic [Ca2+] is kept low (<500 nm) by high cytosolic Ca2+ buffer or strong plasma membrane calcium clearance mechanisms under physiological external [Ca2+].Mitochondrial Ca2+ release (MCR) does not alter the global presynaptic Ca2+ transients.MCR during HFS enhances short‐term facilitation and steady state excitatory postsynaptic currents by increasing vesicular release probability.The intra‐train MCR may provide residual calcium at interspike intervals, and thus support high frequency neurotransmission at central glutamatergic synapses. Emerging evidence indicates that mitochondrial Ca2+ buffering contributes to local regulation of synaptic transmission. It is unknown, however, whether mitochondrial Ca2+ release (MCR) occurs during high frequency synaptic transmission. Confirming the previous notion that 2 μm tetraphenylphosphonium (TPP+) is a specific inhibitor of the mitochondrial Na+/Ca2+ exchanger (mNCX), we studied the role of MCR via mNCX in short‐term plasticity during high frequency stimulation (HFS) at the calyx of Held synapse of the rat. TPP+ reduced short‐term facilitation (STF) and steady state excitatory postsynaptic currents during HFS at mature calyx synapses under physiological extracellular [Ca2+] ([Ca2+]o = 1.2 mm), but not at immature calyx or at 2 mm [Ca2+]o. The inhibitory effects of TPP+ were stronger at synapses with morphologically complex calyces harbouring many swellings and at 32°C than at simple calyx synapses and at room temperature. These effects of TPP+ on STF were well correlated with those on the presynaptic mitochondrial [Ca2+] build‐up during HFS. Mitochondrial [Ca2+] during HFS was increased by TPP+ at mature calyces under 1.2 mm [Ca2+]o, and further enhanced at 32°C, but not under 2 mm [Ca2+]o or at immature calyces. The close correlation of the effects of TPP+ on mitochondrial [Ca2+] with those on STF suggests that mNCX contributes to STF at the calyx of Held synapses. The intra‐train MCR enhanced vesicular release probability without altering global presynaptic [Ca2+]. Our results suggest that MCR during HFS elevates local [Ca2+] near synaptic sites at interspike intervals to enhance STF and to support stable synaptic transmission under physiological [Ca2+]o. Key points: Presynaptic mitochondria not only absorb but also release Ca2+ during high frequency stimulation (HFS) when presynaptic [Ca2+] is kept low (<500 nm) by high cytosolic Ca2+ buffer or strong plasma membrane calcium clearance mechanisms under physiological external [Ca2+].Mitochondrial Ca2+ release (MCR) does not alter the global presynaptic Ca2+ transients.MCR during HFS enhances short‐term facilitation and steady state excitatory postsynaptic currents by increasing vesicular release probability.The intra‐train MCR may provide residual calcium at interspike intervals, and thus support high frequency neurotransmission at central glutamatergic synapses. [ABSTRACT FROM AUTHOR]

Optogenetic manipulations have transformed neuroscience in recent years. While sophisticated tools now exist for controlling the firing patterns of neurons, it remains challenging to optogenetically define the plasticity state of individual synapses. A variety of synapses in the mammalian brain express presynaptic long‐term potentiation (LTP) upon elevation of presynaptic cyclic adenosine monophosphate (cAMP), but the molecular expression mechanisms as well as the impact of presynaptic LTP on network activity and behavior are not fully understood. In order to establish optogenetic control of presynaptic cAMP levels and thereby presynaptic potentiation, we developed synaptoPAC, a presynaptically targeted version of the photoactivated adenylyl cyclase bPAC. In cultures of hippocampal granule cells of Wistar rats, activation of synaptoPAC with blue light increased action potential‐evoked transmission, an effect not seen in hippocampal cultures of non‐granule cells. In acute brain slices of C57BL/6N mice, synaptoPAC activation immediately triggered a strong presynaptic potentiation at mossy fiber synapses in CA3, but not at Schaffer collateral synapses in CA1. Following light‐triggered potentiation, mossy fiber transmission decreased within 20 min, but remained enhanced still after 30 min. The optogenetic potentiation altered the short‐term plasticity dynamics of release, reminiscent of presynaptic LTP. Our work establishes synaptoPAC as an optogenetic tool that enables acute light‐controlled potentiation of transmitter release at specific synapses in the brain, facilitating studies of the role of presynaptic potentiation in network function and animal behavior in an unprecedented manner. Read the Editorial Highlight for this article on page 270. [ABSTRACT FROM AUTHOR]

SUMOylation is a post‐translational modification that regulates protein signalling and complex formation by adjusting the conformation or protein–protein interactions of the substrate protein. There is a compelling and rapidly expanding body of evidence that, in addition to SUMOylation of nuclear proteins, SUMOylation of extranuclear proteins contributes to the control of neuronal development, neuronal stress responses and synaptic transmission and plasticity. In this brief review we provide an update of recent developments in the identification of synaptic and synapse‐associated SUMO target proteins and discuss the cell biological and functional implications of these discoveries. [ABSTRACT FROM AUTHOR]

Insulin signaling through the insulin receptor has long been studied in classic target organs, such as adipose tissue and skeletal muscle, where one of its effects is to increase glucose uptake. Insulin and insulin receptor are present in many areas of the brain, but the functions of brain insulin signaling outside feeding circuits are not well defined. It has been proposed that hippocampal insulin signaling is important for memory, that brain insulin signaling is deficient in Alzheimer's disease, and that intranasal insulin treatment improves cognition, but the mechanisms remain unclear and do not seem to involve increased glucose uptake by neurons. The molecular behavior of the insulin receptor itself is not well known in living neurons; therefore, we investigated the spatial dynamics of the insulin receptor on somatodendritic membranes of live rat hippocampal neurons in culture. Using single‐molecule tracking of quantum dot‐tagged insulin receptors and single‐particle tracking photoactivation localization microscopy, we show that the insulin receptor is distributed over both dendritic shafts and spines. Using colocalization with synaptic markers, we also show that in contrast to the glutamate receptor subunit glutamate receptor subunit A1, the dynamics of the insulin receptor are not affected by association with excitatory synapses; however, the insulin receptor is immobilized by components of inhibitory synapses. The mobility of the insulin receptor is reduced both by low concentrations of the pro‐inflammatory cytokine tumor necrosis factor α and by cholesterol depletion, suggesting an association with sphingolipid‐rich membrane domains. On the other hand, the insulin receptor dynamics in hippocampal neurons are not affected by increased excitatory signaling. Finally, using real‐time single‐event quantification, we find evidence of strong insulin receptor exocytosis on dendritic shafts. Our results suggest an association of the neuronal insulin receptor with specific elements of the dendritic shaft, rather than excitatory synapses. [ABSTRACT FROM AUTHOR]

Anxiety disorder is a common psychiatric disease. Roman chamomile as medicine or tea has long been used as a mild tranquilizer to reduce anxiety, but the mechanism is unclear. This research is based on network pharmacology combined with database mining to find the ingredients, action pathways and key targets of Roman chamomile for the treatment of anxiety. About 126 common targets related to chamomile and anxiety were obtained, and these targets were involved in 56 KEGG pathways. GEO screened LRRK2 as a key protein, and molecular docking showed that the protein could stably bind to drug components. Roman chamomile has the characteristics of multi‐target and multi‐pathway in the treatment of anxiety disorder. Its possible mechanism is to intervene anxiety disorder in the process of disease development, such as neuroactive ligand‐receptor interaction, serotonin synapse, and cAMP signaling pathway. LRRK2 may be an important gene for Roman chamomile in the treatment of anxiety disorder. Practical applications: Roman chamomile is well known for its use in medicine and tea making. It contains many nutrients, which can relieve people's anxiety, help sleep, antibacterial and anti‐inflammatory. In this article, through network pharmacology combined with Gene Expression Omnibus data mining and molecular docking, the target and mechanism of Roman chamomile in the treatment of anxiety were discussed, and its efficacy was verified by model animals, which not only clarified its mechanism at the systematic level, but also proved to be effective at the biological level. It provides a reference for the further development and utilization of Roman chamomile. [ABSTRACT FROM AUTHOR]

Traditional von Neumann computing architecture with separated computation and storage units has already impeded the data processing performance and energy efficiency, calling for emerging neuromorphic electronic and optical devices and systems which can mimic the human brain to shift this paradigm. Material‐level innovation has become the key component to this revolution of information technology. Chalcogenide phase‐change material (PCM) as a well‐acknowledged data‐storage medium is a promising candidate to tackle this challenge. In this review, the use of PCMs to implement artificial neurons and synapses from both the electronic and optical respects is discussed, and in particular, the structure–property physics and transition dynamics that enable such brain‐inspired and in‐memory computing applications are emphasized. Recent advances on the atomic‐level amorphous and crystalline structures, transition mechanisms, materials optimization and design, neural and synaptic devices, brain‐inspired chips, and computing systems, as well as the future opportunities of PCMs, are summarized and discussed. [ABSTRACT FROM AUTHOR]

Action potentials trigger two modes of neurotransmitter release, with a fast synchronous component and a temporally delayed asynchronous release. Asynchronous release contributes to information transfer at synapses, including at the hippocampal mossy fiber (MF) to CA3 pyramidal cell synapse where it controls the timing of postsynaptic CA3 pyramidal neuron firing. Here, we identified and characterized the main determinants of asynchronous release at the MF–CA3 synapse. We found that asynchronous release at MF–CA3 synapses can last on the order of seconds following repetitive MF stimulation. Elevating the stimulation frequency or the external Ca2+ concentration increased the rate of asynchronous release, thus, arguing that presynaptic Ca2+ dynamics is the major determinant of asynchronous release rate. Direct MF bouton Ca2+ imaging revealed slow Ca2+ decay kinetics of action potential (AP) burst‐evoked Ca2+ transients. Finally, we observed that asynchronous release was preferentially mediated by Ca2+ influx through P/Q‐type voltage‐gated Ca2+ channels, while the contribution of N‐type VGCCs was limited. Overall, our results uncover the determinants of long‐lasting asynchronous release from MF terminals and suggest that asynchronous release could influence CA3 pyramidal cell firing up to seconds following termination of granule cell bursting. [ABSTRACT FROM AUTHOR]

Broad issues associated with non-replicability have been described in experimental pharmacological and behavioral cognitive studies. Efforts to prevent biases that contribute to non-replicable scientific protocols and to improve experimental rigor for reproducibility are increasingly seen as a basic requirement for the integrity of scientific research. Synaptic plasticity, encompassing long-term potentiation (LTP), is believed to underlie mechanisms of learning and memory. The present study was undertaken in Long-Evans (LE) rats, a strain of rat commonly used in cognitive behavioral tests, to (1) compare three LTP tetanisation protocols, namely, the high-frequency stimulation (HFS), the theta-burst stimulation (TBS), and the paired-pulse facilitation (PPF) at the Schaffer collateral-CA1 stratum radiatum synapse and to (2) assess sensitivity to acute pharmacology. Results: (1) When compared to Sprague-Dawley (SD) rats, the HFS using a stimulus intensity of 50% of the maximum slope obtained from input/output (I/O) curves elicited lower and higher thresholds of synaptic plasticity responses in SD and LE rats, respectively. The 2-train TBS protocol significantly enhanced the LTP response in LE rats over the 5- and 10-train TBS protocols in both strains, and the 5 × TBS protocol inducing a subthreshold LTP response was used in subsequent pharmacological studies in LE rats. The PPF protocol, investigating the locus of the LTP response, showed no difference for the selected interstimulus intervals. (2) Scopolamine, a nonspecific muscarinic antagonist, had a subtle effect, whereas donepezil, an acetylcholinesterase inhibitor, significantly enhanced the LTP response, demonstrating the sensitivity of the TBS protocol to enhanced cholinergic tone. MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, significantly reduced LTP response, while memantine, another NMDA antagonist, had no effect on LTP response, likely associated with a weaker TBS protocol. PQ10, a phosphodiesterase-10 inhibitor, significantly enhanced the TBS-induced LTP response, but did not change the PPF response. Overall, the results confirm the strain-dependent differences in the form of synaptic plasticity, replicate earlier plasticity results, and report effective protocols that generate a relatively subthreshold margin of LTP induction and maintenance, which are suitable for pharmacology in the LE rat strain mainly used in cognitive studies. [ABSTRACT FROM AUTHOR]

The anatomy and physiology of monosynaptic connections in rodent hippocampal CA1 have been extensively studied in recent decades. Yet, the resulting knowledge remains disparate and difficult to reconcile. Here, we present a data‐driven approach to integrate the current state‐of‐the‐art knowledge on the synaptic anatomy and physiology of rodent hippocampal CA1, including axo‐dendritic innervation patterns, number of synapses per connection, quantal conductances, neurotransmitter release probability, and short‐term plasticity into a single coherent resource. First, we undertook an extensive literature review of paired recordings of hippocampal neurons and compiled experimental data on their synaptic anatomy and physiology. The data collected in this manner is sparse and inhomogeneous due to the diversity of experimental techniques used by different groups, which necessitates the need for an integrative framework to unify these data. To this end, we extended a previously developed workflow for the neocortex to constrain a unifying in silico reconstruction of the synaptic physiology of CA1 connections. Our work identifies gaps in the existing knowledge and provides a complementary resource toward a more complete quantification of synaptic anatomy and physiology in the rodent hippocampal CA1 region. [ABSTRACT FROM AUTHOR]

Key points: Age‐related hearing loss (ARHL) is associated with the loss of inner hair cell (IHC) ribbon synapses, lower hearing sensitivity and decreased ability to understand speech, especially in a noisy environment.Little is known about the age‐related physiological and morphological changes that occur at ribbon synapses.We show that the differing degrees of ARHL in four selected mouse stains is correlated with the loss of ribbon synapses, being most severe for the strains C57BL/6NTac and C57BL/6J, less so for C57BL/6NTacCdh23+‐Repaired and lowest for C3H/HeJ.Despite the loss of ribbon synapses with age, the volume of the remaining ribbons increased and the size and kinetics of Ca2+‐dependent exocytosis in IHCs was unaffected, indicating the presence of a previously unknown degree of functional compensation at ribbon synapses.Although the age‐related morphological changes at IHC ribbon synapses contribute to the different progression of ARHL, without the observed functional compensation hearing loss could be greater. Mammalian cochlear inner hair cells (IHCs) are specialized sensory receptors able to provide dynamic coding of sound signals. This ability is largely conferred by their ribbon synapses, which tether a large number of vesicles at the IHC's presynaptic active zones, allowing high rates of sustained synaptic transmission onto the afferent fibres. How the physiological and morphological properties of ribbon synapses change with age remains largely unknown. Here, we have investigated the biophysical and morphological properties of IHC ribbon synapses in the ageing cochlea (9–12 kHz region) of four mouse strains commonly used in hearing research: early‐onset progressive hearing loss (C57BL/6J and C57BL/6NTac) and 'good hearing' strains (C57BL/6NTacCdh23+ and C3H/HeJ). We found that with age, both modiolar and pillar sides of the IHC exhibited a loss of ribbons, but there was an increased volume of those that remained. These morphological changes, which only occurred after 6 months of age, were correlated with the level of hearing loss in the different mouse strains, being most severe for C57BL/6NTac and C57BL/6J, less so for C57BL/6NTacCdh23+ and absent for C3H/HeJ strains. Despite the age‐related reduction in ribbon number in three of the four strains, the size and kinetics of Ca2+‐dependent exocytosis, as well as the replenishment of synaptic vesicles, in IHCs was not affected. The degree of vesicle release at the fewer, but larger, individual remaining ribbon synapses colocalized with the post‐synaptic afferent terminals is likely to increase, indicating the presence of a previously unknown degree of functional compensation in the ageing mouse cochlea. Key points: Age‐related hearing loss (ARHL) is associated with the loss of inner hair cell (IHC) ribbon synapses, lower hearing sensitivity and decreased ability to understand speech, especially in a noisy environment.Little is known about the age‐related physiological and morphological changes that occur at ribbon synapses.We show that the differing degrees of ARHL in four selected mouse stains is correlated with the loss of ribbon synapses, being most severe for the strains C57BL/6NTac and C57BL/6J, less so for C57BL/6NTacCdh23+‐Repaired and lowest for C3H/HeJ.Despite the loss of ribbon synapses with age, the volume of the remaining ribbons increased and the size and kinetics of Ca2+‐dependent exocytosis in IHCs was unaffected, indicating the presence of a previously unknown degree of functional compensation at ribbon synapses.Although the age‐related morphological changes at IHC ribbon synapses contribute to the different progression of ARHL, without the observed functional compensation hearing loss could be greater. [ABSTRACT FROM AUTHOR]

The implementation of memristors that are wearable and transparent has attracted significant attention. However, the development of high‐performance memristors that simultaneously possess high flexibility and environmental stability has remained a tremendous challenge suffering from limited choice of materials with both good ion‐electron mobility and structural flexibility. Inspired by the unique poly‐ionic nature of ammonium polyphosphate (APP), a novel Au/APP/ITO memristor with favorable flexibility and stability is prepared. Synaptic behaviors can be stimulated by voltage pulses that are 20 ns in width, 0.1 V in amplitude, and repeatable under 104 pulse cycles, thereby outperforming several other benchmark memristors. Further, the device, prepared on conductive silicone, can sustain its synaptic performance even under 360° bending. Furthermore, the device can sustain its synaptic behaviors even after exposure to fire for 60 s and 5.6 kGy of ionic irradiation. Additionally, APP is determined to be nontoxic, biodegradable, and transparent when compared with all the organics and inorganics used in previous memristors. The results of this study will inspire the development of more inorganic polymers for their utilization in future environmentally stable and flexible electronics. [ABSTRACT FROM AUTHOR]

The SynGAP protein is a major regulator of synapse biology and neural circuit function. Genetic variants linked to epilepsy and intellectual disability disrupt synaptic function and neural excitability. SynGAP has been involved in multiple signaling pathways and can regulate small GTPases with very different roles. Yet, the molecular bases behind this pleiotropy are poorly understood. We hypothesize that different SynGAP isoforms will mediate different sets of functions and that deciphering their spatio‐temporal expression and subcellular localization will accelerate understanding their multiple functions. Using isoform‐specific antibodies recognizing SynGAP in mouse and human samples we found distinctive developmental expression patterns for all SynGAP isoforms in five mouse brain areas. Particularly noticeable was the delayed expression of SynGAP‐α1 isoforms, which directly bind to postsynaptic density‐95, in cortex and hippocampus during the first 2 weeks of postnatal development. Suggesting that during this period other isoforms would have a more prominent role. Furthermore, we observed subcellular localization differences between isoforms, particularly throughout postnatal development. Consistent with previous reports, SynGAP was enriched in the postsynaptic density in the mature forebrain. However, SynGAP was predominantly found in non‐synaptic locations in a period of early postnatal development highly sensitive to SynGAP levels. While, α1 isoforms were always found enriched in the postsynaptic density, α2 isoforms changed from a non‐synaptic to a mostly postsynaptic density localization with age and β isoforms were always found enriched in non‐synaptic locations. The differential expression and subcellular distribution of SynGAP isoforms may contribute to isoform‐specific regulation of small GTPases, explaining SynGAP pleiotropy. [ABSTRACT FROM AUTHOR]

Key points: We simulate the unitary local field potential (uLFP) generated in the hippocampus CA3, using morphologically detailed models.The model suggests that cancelling effects between apical and basal dendritic synapses explain the low amplitude of excitatory uLFPs.Inhibitory synapses around the soma do not cancel and could explain the high‐amplitude inhibitory uLFPs.These results suggest that somatic inhibition constitutes a strong component of LFPs, which may explain a number of experimental observations. Synaptic currents represent a major contribution to the local field potential (LFP) in brain tissue, but the respective contribution of excitatory and inhibitory synapses is not known. Here, we provide estimates of this contribution by using computational models of hippocampal pyramidal neurons, constrained by in vitro recordings. We focus on the unitary LFP (uLFP) generated by single neurons in the CA3 region of the hippocampus. We first reproduce experimental results for hippocampal basket cells, and in particular how inhibitory uLFP are distributed within hippocampal layers. Next, we calculate the uLFP generated by pyramidal neurons, using morphologically reconstructed CA3 pyramidal cells. The model shows that the excitatory uLFP is of small amplitude, smaller than inhibitory uLFPs. Indeed, when the two are simulated together, inhibitory uLFPs mask excitatory uLFPs, which might create the illusion that the inhibitory field is generated by pyramidal cells. These results provide an explanation for the observation that excitatory and inhibitory uLFPs are of the same polarity, in vivo and in vitro. These results suggest that somatic inhibitory currents are large contributors to the LFP, which is important information for interpreting this signal. Finally, the results of our model might form the basis of a simple method to compute the LFP, which could be applied to point neurons for each cell type, thus providing a simple biologically grounded method for calculating LFPs from neural networks. In conclusion, computational models constrained by in vitro recordings suggest that: (1) Excitatory uLFPs are of smaller amplitude than inhibitory uLFPs. (2) Inhibitory uLFPs form the major contribution to LFPs. (3) uLFPs can be used as a simple model to generate LFPs from spiking networks. Key points: We simulate the unitary local field potential (uLFP) generated in the hippocampus CA3, using morphologically detailed models.The model suggests that cancelling effects between apical and basal dendritic synapses explain the low amplitude of excitatory uLFPs.Inhibitory synapses around the soma do not cancel and could explain the high‐amplitude inhibitory uLFPs.These results suggest that somatic inhibition constitutes a strong component of LFPs, which may explain a number of experimental observations. [ABSTRACT FROM AUTHOR]