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Synapses are highly specialized neuronal structures that are essential for neurotransmission, and they are dynamically regulated throughout the lifetime. Although accumulating evidence indicates that these structures are crucial for information processing and storage in the brain, their precise roles beyond neurotransmission are yet to be fully appreciated. Genetically encoded fluorescent tools have deepened our understanding of synaptic structure and function, but developing an ideal methodology to selectively visualize, label and manipulate synapses remains challenging. Here, we provide an overview of currently available synapse labelling techniques and describe their extension to enable synapse manipulation. We categorize these approaches on the basis of their conceptual bases and target molecules, compare their advantages and limitations and propose potential modifications to improve their effectiveness. These methods have broad utility, particularly for investigating mechanisms of synaptic function and synaptopathy., (© 2024. Springer Nature Limited.)

The results of comparative morphological and ultrastructural research of the synaptic organization of spinal cord motoneurons from fishes, amphibian, reptiles and mammals are presented in the review. Fundamental regularities of the formation of the synaptic organization of motoneurons in vertebrate phylogenesis were established. The results of electron microscopical analysis showed that all basic elements of the synaptic ultrastructure preserved in the motoneuronal synapse of vertebrates during the evolution. On the basis of large experimental material it was found that the synaptic organization of individual motoneuron as a whole underwent structural reorganization, presented as corresponding transformations in mechanisms of the synaptic transmission.

A deep understanding of how the brain controls behaviour requires mapping neural circuits down to the muscles that they control. Here, we apply automated tools to segment neurons and identify synapses in an electron microscopy dataset of an adult female Drosophila melanogaster ventral nerve cord (VNC) 1 , which functions like the vertebrate spinal cord to sense and control the body. We find that the fly VNC contains roughly 45 million synapses and 14,600 neuronal cell bodies. To interpret the output of the connectome, we mapped the muscle targets of leg and wing motor neurons using genetic driver lines 2 and X-ray holographic nanotomography 3 . With this motor neuron atlas, we identified neural circuits that coordinate leg and wing movements during take-off. We provide the reconstruction of VNC circuits, the motor neuron atlas and tools for programmatic and interactive access as resources to support experimental and theoretical studies of how the nervous system controls behaviour., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Epilepsy is one of the most represented neurological diseases worldwide. However, in many cases, the precise molecular mechanisms of epileptogenesis and ictiogenesis are unknown. Because of their important role in synaptic function and neuronal excitability, NMDA receptors are implicated in various epileptogenic mechanisms. Most of these are subunit specific and require a precise analysis of the subunit composition of the NMDARs implicated. Here, we describe an express electrophysiological method to analyze the contribution of NMDAR subunits to spontaneous postsynaptic activity in identified cells in brain slices using patch clamp whole cell recordings., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Memristors have recently attracted significant interest due to their applicability as promising building blocks of neuromorphic computing and electronic systems. The dynamic reconfiguration of memristors, which is based on the history of applied electrical stimuli, can mimic both essential analog synaptic and neuronal functionalities. These can be utilized as the node and terminal devices in an artificial neural network. Consequently, the ability to understand, control, and utilize fundamental switching principles and various types of device architectures of the memristor is necessary for achieving memristor-based neuromorphic hardware systems. Herein, a wide range of memristors and memristive-related devices for artificial synapses and neurons is highlighted. The device structures, switching principles, and the applications of essential synaptic and neuronal functionalities are sequentially presented. Moreover, recent advances in memristive artificial neural networks and their hardware implementations are introduced along with an overview of the various learning algorithms. Finally, the main challenges of the memristive synapses and neurons toward high-performance and energy-efficient neuromorphic computing are briefly discussed. This progress report aims to be an insightful guide for the research on memristors and neuromorphic-based computing., (© 2020 Wiley-VCH GmbH.)

In vertebrates, stimulus-independent activity accompanies neural circuit maturation throughout the developing brain 1,2 . The recent discovery of similar activity in the developing Drosophila central nervous system suggests that developmental activity is fundamental to the assembly of complex brains 3 . How such activity is coordinated across disparate brain regions to influence synaptic development at the level of defined cell types is not well understood. Here we show that neurons expressing the cation channel transient receptor potential gamma (Trpγ) relay and pattern developmental activity throughout the Drosophila brain. In trpγ mutants, activity is attenuated globally, and both patterns of activity and synapse structure are altered in a cell-type-specific manner. Less than 2% of the neurons in the brain express Trpγ. These neurons arborize throughout the brain, and silencing or activating them leads to loss or gain of brain-wide activity. Together, these results indicate that this small population of neurons coordinates brain-wide developmental activity. We propose that stereotyped patterns of developmental activity are driven by a discrete, genetically specified network to instruct neural circuit assembly at the level of individual cells and synapses. This work establishes the fly brain as an experimentally tractable system for studying how activity contributes to synapse and circuit formation., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

For many decades, the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here, we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum and might also play a role in development. We then consider the potential problems and benefits of it having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, and variable complex spike waveforms) make it more or less suitable for one or the other of these functions, and why having multiple functions makes sense from an evolutionary perspective. We did not attempt to reach a consensus on the specific role(s) the olivocerebellar system plays in different types of movements, as that will ultimately be determined experimentally; however, collectively, the various contributions highlight the flexibility of the olivocerebellar system, and thereby suggest that it has the potential to act in both the motor learning and motor control functions of the cerebellum. [ABSTRACT FROM AUTHOR]

Multiple studies have reported the observation of electro-synaptic response in different metal/insulator/metal devices. However, most of them analyzed large (>1 µm 2 ) devices that do not meet the integration density required by industry (10 10  devices/mm 2 ). Some studies emploied a scanning tunneling microscope (STM) to explore nano-synaptic response in different materials, but in this setup there is a nanogap between the insulator and one of the metallic electrodes (i.e., the STM tip), not present in real devices. Here, it is demonstrated how to use conductive atomic force microscopy to explore the presence and quality of nano-synaptic response in confined areas <50 nm 2 . Graphene oxide (GO) is selected due to its easy fabrication. Metal/GO/metal nano-synapses exhibit potentiation and paired pulse facilitation with low write current levels <1 µA (i.e., power consumption ≈3 µW), controllable excitatory post-synaptic currents, and long-term potentiation and depression. The results provide a new method to explore nano-synaptic plasticity at the nanoscale, and point to GO as an important candidate for the fabrication of ultrasmall (<50 nm 2 ) electronic synapses fulfilling the integration density requirements of neuromorphic systems., (© 2021 Wiley-VCH GmbH.)

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 (GABA A Rs). 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 GABA A Rs. 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., (© 2020 International Society for Neurochemistry.)

Microglia are the resident immune cells of the central nervous system, and are important for cellular processes. In addition to their classical roles in pathophysiological conditions, these immune cells also dynamically interact with neurons and influence their structure and function in physiological conditions. Microglia have been shown to contact neurons at various points, including the dendrites, cell bodies, synapses, and axons, and support various developmental functions, such as neuronal survival, axon elongation, and maturation of the synaptic circuit. This review summarizes the current knowledge regarding the roles of microglia in brain development, with particular emphasis on microglia-axon interactions. We will review recent findings regarding the functions and signaling pathways involved in the reciprocal interactions between microglia and neurons. Moreover, as these interactions are altered in disease and injury conditions, we also discuss the effect and alteration of microglia-axon interactions in disease progression and the potential role of microglia in developmental brain disorders.

Climbing fibers from the inferior olive make strong excitatory synapses onto cerebellar Purkinje cell (PC) dendrites and trigger distinctive responses known as complex spikes. We found that, in awake mice, a complex spike in one PC suppressed conventional simple spikes in neighboring PCs for several milliseconds. This involved a new ephaptic coupling, in which an excitatory synapse generated large negative extracellular signals that nonsynaptically inhibited neighboring PCs. The distance dependence of complex spike-simple spike ephaptic signaling, combined with the known CF divergence, allowed a single inferior olive neuron to influence the output of the cerebellum by synchronously suppressing the firing of potentially over 100 PCs. Optogenetic studies in vivo and dynamic clamp studies in slice indicated that such brief PC suppression, as a result of either ephaptic signaling or other mechanisms, could effectively promote firing in neurons in the deep cerebellar nuclei with remarkable speed and precision.

Artificial neurons with bio-inspired firing patterns have the potential to significantly improve the performance of neural network computing. The most significant component of an artificial neuron circuit is a large amount of energy consumption. Recent literature has proposed memristors as a promising option for synaptic implementation. In contrast, implementing memristive circuitry through neuron hardware presents significant challenges and is a relevant research topic. This paper describes an efficient circuit-level mixed CMOS memristor artificial neuron network with a memristor synapse model. From this perspective, the paper describes the design of artificial neurons in standard CMOS technology with low power utilization. The neuron circuit response is a modified version of the Morris-Lecar theoretical model. The suggested circuit employs memristor-based artificial neurons with Dual Transistor and Dual Memristor (DTDM) synapse circuit. The proposed neuron network produces a high spiking frequency and low power consumption. According to our research, a memristor-based Morris Lecar (ML) neuron with a DTDM synapse circuit consumes 12.55 pW of power, the spiking frequency is 22.72 kHz, and 2.13 fJ of energy per spike. The simulations were carried out using the Spectre tool with 45 nm CMOS technology. [ABSTRACT FROM AUTHOR]

Neurodegenerative Tauopathies are a part of several neurological disorders and aging-related diseases including, but not limited to, Alzheimer's Disease, Frontotemporal Dementia with Parkinsonism, and Chronic Traumatic Encephalopathy. The major hallmarks present in these conditions include Tau pathology (composed of hyperphosphorylated Tau tangles) and synaptic loss. in vivo studies linking Tau pathology and mitochondrial alterations at the synapse, an avenue that could lead to synaptic loss, remain predominantly scarce. For this reason, using 3-month-old wild-type and human mutant Tau P301S transgenic mice, we investigated the association of Tau with mitochondria, synaptosome bioenergetics, and characterized excitatory synaptic loss across hippocampal regions (Dentate Gyrus, perisomatic CA3, and perisomatic CA1) and in the parietal cortex. We found a significant loss of excitatory synapses in the parietal cortex and hippocampal Dentate Gyrus (DG) of Tau P301S mice. Furthermore, we found that Tau (total and disease-relevant phosphorylated Tau) associates with both the non-synaptic and synaptic mitochondria of Tau P301S mice and this coincided with synaptic mitochondrial dysfunction. The findings presented here suggest that Tau associates with mitochondria at the synapse, leading to synaptic mitochondrial dysfunction, and likely contributing to synaptic loss., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Heavy alcohol use during adolescence has a significant impact on cognitive functions, such as episodic memory, even after detoxification. However, in animal models, defects in episodic memory by adolescent alcohol exposure have not been consistently replicated, and thus, the brain regions and systems that are involved remain to be elucidated. Here, we show that adolescent alcohol exposure impairs episodic memory through the impairment of the dopamine system in the prelimbic region (PrL) of the medial prefrontal cortex in both females and males. Using mice as a model, we first show that adolescent alcohol exposure disrupts episodic-like memory in female and male adult mice. We then show that adolescent alcohol exposure decreases dopaminergic presynaptic terminals in the PrL in female and male mice. This decrease persists into adulthood. Finally, we show that the adult application of a D1 dopamine receptor agonist into the PrL of adolescent alcohol-exposed mice rescues episodic-like memory in female and male mice. Together, our results identify that dopaminergic synapses in the PrL play critical roles in the effects of adolescent alcohol use on episodic memory and provide a potential strategy to reverse memory deficits caused by adolescent alcohol use in both sexes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cannabis derivatives are among the most widely used psychoactive substances in the world, which leads to growing medical concerns regarding its chronic use and abuse especially among adolescents. Exposure to THC during formative years produces long-term behavioral alterations that share similarities with symptoms of psychiatric and neurodevelopmental disorders. In this study, we have analyzed the functional and molecular mechanisms that might underlie these alterations. Rat organotypic hippocampal slices were cultured for 2 days (immature) or 10 days (mature) in vitro and then exposed for 7 days to THC (1 µM) or CBD (1 µM). At the end of the treatment, slices were analyzed by Western blotting, electrophysiological recordings, RT-PCR, and fluorescence microscopy to explore the molecular and functional changes in the hippocampus. A prolonged (7-day) exposure to THC reduced the expression levels of pre- (synaptophysin, vGlut1) and post-synaptic (PSD95) proteins in both immature and mature slices, whereas CBD significantly increased the expression levels of PSD95 only in immature slices. In addition, THC significantly reduced the passive properties and the intrinsic excitability of membranes and increased sEPSCs in CA1 pyramidal cells of immature but not mature slices. Exposure to both cannabinoids impaired mitochondrial function as detected by the reduction of mRNA expression levels of mitobiogenesis genes such as VDAC1, UCP2, and TFAM. Finally, THC but not CBD caused tissue disorganization and morphological modifications in CA1 pyramidal neurons, astrocytes and microglia in both immature and mature slices. These results are helpful to explain the specific vulnerability of adolescent brain to the effects of psychotropic cannabinoids., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Prenatal virus infection-induced maternal immune activation (MIA) is linked to a greater risk of neurodevelopmental disorders in offspring. Prenatal exposure to poly(I:C) in pregnant mice is a well-established approach to mimic virus infection-induced MIA, leading to neuropsychiatric disorders and aberrant brain development, especially in the medial prefrontal cortex (mPFC). ATPase phospholipid flippase 8A2 (ATP8A2) is the main phospholipid lipase, expressed in the mPFC and is crucial for maintaining cell membrane stability by flipping phosphatidylserine from the outer leaflet to the inner leaflet of the cell membrane. Atp8a2 knockout or mutation causes a series of phenotypes, including impaired neuronal cell survival, neuroinflammation, altered synaptic plasticity, and behavioral abnormalities. These findings suggest that ATP8A2 expression in the mPFC may be impaired in MIA offspring and that the decrease in ATP8A2 expression may be involved in the development of MIA-induced neuropsychiatric disorders in offspring. No reports addressing this issue have been published. Here, after confirming abnormal affective-/social-related behaviors in adulthood and reduced synapse-associated protein expression on the birth day (P0) and the fourth postnatal day (P4) in the mPFC of MIA offspring that were born to dams exposed prenatally to a single dose of poly(I:C) (10 mg/kg, i.p.), decreased ATP8A2 expression was also observed in the mPFC of MIA offspring at P0 and P4.Upregulating ATP8A2 in the mPFC restored synapse-associated protein levels, along with a partial improvement in the behavioral performance of MIA offspring. Upregulation of ATP8A2 also blocked neuronal phosphatidylserine externalization and eliminated the excitation/inhibition (E/I) imbalance in the mPFC of MIA offspring. This study revealed that the low expression of ATP8A2 following MIA exposure may play a role in mediating abnormal brain development and function in offspring. ATP8A2 potentially represents a novel molecule involved in MIA-induced neuropsychiatric disorders in offspring, and may serve as a novel therapeutic target for the intervention of psychiatric disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Astrocytes, which actively participate in cognitive processes, have a complex spongiform morphology, highlighted by extensive ramified fine processes that closely enwrap the pre- and post-synaptic compartments, forming tripartite synapses. However, the role of astrocyte morphology in cognitive processes remains incompletely understood and even controversial. The actin-binding protein Ezrin is highly expressed in astrocytes and is a key structural determinant of astrocyte morphology. Here, we found that Ezrin expression and astrocyte fine process volume in the hippocampus of male mice increased after learning but decreased after lipopolysaccharide injection and in a mouse model of postoperative cognitive dysfunction, both of which involved models with impaired cognitive function. Additionally, astrocytic Ezrin knock-out led to significantly decreased astrocytic fine process volumes, decreased astrocyte-neuron proximity, and induced anxiety-like behaviors and cognitive dysfunction. Astrocytic Ezrin deficiency in the hippocampus was achieved by using a microRNA silencing technique delivered by adeno-associated viruses. Down-regulation of Ezrin in hippocampal astrocytes led to disrupted astrocyte-synapse interactions and impaired synaptic functions, including synaptic transmission and synaptic plasticity, which could be rescued by exogenous administration of D-serine. Remarkably, decreased Ezrin expression and reduced astrocyte fine processes volumes were also observed in aged mice with decreased cognitive function. Moreover, overexpression of astrocytic Ezrin increased astrocyte fine process volumes and improved cognitive function in aged mice. Overall, our results indicate Ezrin-mediated astrocyte fine processes integrity shapes astrocyte-synapse signaling contributing to cognitive function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Flame retardant polybrominated diphenyl ethers (PBDEs) accumulate in human bodies through food and dust ingestion, and cause neurobehavioral deficits with obscure mechanism. We aimed to investigate NMDAR-CaMKⅡγ-mediated synapse-to-nuclear communication involved in BDE-209-induced cognitive impairment, and alleviation from exogenous melatonin. Decreased NMDAR subunits GluN2A and 2B, autophosphorylation of CaMKⅡα, and postsynaptic GluA1 trafficking were observed in the hippocampus of juvenile rats after maternal BDE-209 exposure. Moreover, nuclear shuttling of CaMKⅡγ with CaM, as well as downstream nuclear p-CaMKIV and p-CREB-dependent genes (Bdnf, c-Fos, Arc) expression were all causally down-regulated. These resulted in less dendritic spines in CA1 area and poor spatial learning and memory. Importantly, elevated miR-219a-5p in transcriptome sequencing was identified together with its targets Grin2b and Camk2g mRNA, further elucidated the reduction in GluN2B and CaMKⅡγ protein. These changes on synaptic plasticity caused by BDE-209 were reversed correspondingly under pretreatment of melatonin, partially via miR-219a inhibition. Collectively, our findings suggest that synaptonuclear signaling alterations potentially mediated neurobehavioral deficits induced by early-life BDE-209 exposure and the neuroprotection from melatonin, therefore provided a novel perspective for prevention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. On behalf of all co-authors, I would like to declare this work was original research that has not been published previously nor being considered for publication elsewhere, in whole or in part. No conflicts of interest exists in the submission of this manuscript. All other authors have read the manuscript and have agreed to submit it in its current form for consideration for publication in Food and Chemical Toxicology., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Depression is a prevalent mental illness that significantly impairs individuals' overall quality of life and physical well-being. However, the pathological mechanisms of depression remain unclear, and effective treatment strategies are urgently needed. Pentraxin 3 (PTX3), a long pentraxin protein, plays a significant role in various pathological conditions, including infections, immune responses, and tissue repair. In this study, we collected serum from patients with depression and established both animal and cell models of depression. We found that PTX3 expression was significantly reduced in both the serum of patients with depression and the hippocampus of chronic unpredictable mild stress (CUMS) mice. PTX3 supplementation markedly improved depressive-like behavior in CUMS mice and promoted microglial M2 polarization. In the LPS-induced BV2 cell model, PTX3 overexpression facilitated microglial M2 polarization via activation of the CREB/CEBPb axis. Additionally, PTX3 enhanced fibroblast growth factor 22 (FGF22) expression and excitatory synapse formation in the CA3 region of the hippocampus in CUMS mice. In the dexamethasone (DXM)-treated SH-SY5Y cell model, PTX3 overexpression increased SPI1 expression, elevated FGF22 transcriptional activity, and promoted the expression of excitatory synapse-related proteins PSD95 and VGLUT1. In summary, our study demonstrates that PTX3 promotes microglial M2 polarization and excitatory synapse formation in the hippocampus, suggesting potential antidepressant effects and providing theoretical support for considering PTX3 as a therapeutic target for depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cadmium (Cd), a notorious environmental pollutant, has been linked to neurological disorders, but the underlying mechanism remains elusive. We aimed to explore the role of microglia in Cd-induced synaptic damages at environmentally relevant doses and whether microglia directly engulf synaptic structures. Nrf2 is deeply implicated in the status of microglial activation; therefore, we also investigated whether it is involved in the above process. Nrf2 knockout mice and wild-type mice were used to explore prolonged Cd exposure-induced synaptic damages, learning-memory impairments, and microglial activation. We also created Nrf2 knockdown (KD) BV2 microglia to investigate the role of cell-specific Nrf2 in Cd-induced microglial activation. Finally, we developed co-culture systems of either Nrf2-KD or Scramble microglia and primary neurons or HT22 neurons to study the effects of Nrf2-regulated microglial activation on synaptic damages induced by Cd. Moreover, the direct engulfment, a main avenue in microglia that may be responsible for Cd-induced synaptic damages and regulated by Nrf2, was specifically studied in vivo and in vitro, along with underlying specific mechanisms. We found that Cd exposure induced microglial overactivation, and Cd-overactivated microglia impaired synapses through direct engulfment of synaptic structures, which may contribute to learning-memory impairments. Both fractalkine and complement pathways underlay microglial engulfment of synapses due to Cd exposure. Nrf2 was essential in preventing microglial overactivation and subsequent direct engulfment, thus preventing the consequent synaptic damages due to Cd exposure. Overall, the findings suggest that Cd-overactivated microglia damage synapses through direct engulfment, resulting from the activation of fractalkine and complement pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is characterized by the accumulation of soluble amyloid-β oligomers (AβOs) in the brain, which disrupt synaptic function and promote cognitive decline. Here, we investigated the effects of AβOs on excitatory and inhibitory synaptic transmission and plasticity by performing stereotaxic injections of AβOs directly into the hippocampal CA1 region, followed by hippocampal slice isolation for electrophysiological measurements. AβOs injections altered basal excitatory synaptic transmission, reducing field excitatory postsynaptic potentials (fEPSPs) and impairing excitatory long-term potentiation (LTP). Additionally, AβOs injections significantly increased basal inhibitory synaptic transmission, as evidenced by the increased amplitude of field inhibitory postsynaptic potentials (fIPSPs), but impaired the induction and maintenance of inhibitory long-term potentiation (iLTP). Accordingly, we propose that AβOs injections induce the saturation of the GABAergic system and thus disrupt the hippocampal excitatory-inhibitory balance. These findings highlight the dual impact of AβOs on both excitatory and inhibitory synapses, generating synaptic dysregulation and possibly worsening cognitive decline in AD. Understanding these mechanisms could provide new insights for developing therapies to restore synaptic balance and hippocampal function in AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Sterile Alpha and TIR Motif Containing 1 (SARM1) are proteins implicated in various neurological processes; however, their role in depression remains unexplored. This study investigated the contribution of SARM1 to depressive-like behaviors in a chronic stress-induced depression model and SARM1 knockout (KO) mice. Depressive-like behaviors were assessed using a battery of behavioral tests, including the Open Field Test (OFT), the Forced Swim Test (FST), the Sucrose Preference Test (SPT), and the Tail Suspension Test (TST). Mitochondrial energy metabolism alteration, cytokine level changes, and other related molecular signaling protein expression were evaluated using ELISA and western blotting techniques to investigate the underlying mechanisms. Behavioral assessments (OFT, FST, SPT, TST) revealed depressive-like phenotypes in SARM1 KO mice, accompanied by altered mitochondrial energy metabolism (NAD+, ATP) in the cortex. Intriguingly, SARM1 depletion led to peripheral inflammation, as evidenced by elevated cytokine levels in plasma but not in brain regions (cortex). In addition, we found dysregulated energy metabolism, AMPK signaling, and synaptic plasticity in the cortex of SARM1 KO mice. Notably, AICAR (Acadesine), an AMPK activator, ameliorated depressive-like behaviors and synaptic dysfunction, while Compound C, an AMPK inhibitor, reversed these effects. Additionally, NH125, an eEF2 kinase inhibitor, improved depressive-like behaviors in SARM1 KO mice. These findings demonstrate that SARM1 is critical in regulating depressive-like behaviours through the AMPKα/p-eEF2 signaling pathway. Targeting AMPK signaling and synaptic function may offer novel therapeutic avenues for depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Subchronic exposure to cyanuric acid (CA) and its structural analogue melamine induces long-term effects on brain and behavior in male rodents. To examine if this exposure induced negative effects on cognitive function in females, we examined the behavioral performance and further attempted to investigate synaptic and neuronal function. CA was intraperitoneal treated with 20 or 40 mg/kg/day to adolescent female rats for 4 consecutive weeks. Multiple behavioral tests were employed to assess spatial cognition, learning strategy, locomotion and motivation. Hippocampal synaptic function at Schaffer collaterals-CA1 synapses and excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons was evaluated. Meanwhile, the glutamate transport inhibitor DL-threo-β-benzyloxyaspartate (DL-TBOA) was infused into hippocampal CA1 region to certify the underlying mechanism. We found that subchronic CA exposure impairs reversal learning ability with dose-dependent effects but did not affect spatial learning and memory, or learning strategy. The expression and phosphorylation of N-methyl-D-aspartate receptor (NMDAR) GluN2B subunits were simultaneously reduced in the hippocampus and the GluN2B-mediated synaptic function, including long-term depression (LTD) and paired-pulse facilitation (PPF), was suppressed. CA could also diminish postsynaptic density protein-95 (PSD-95) expression but did change the levels of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) GluA1 or NMDAR GluN2A subunit, or hippocampal spine density. Meanwhile, CA depressed frequency and amplitude of GluN2B-mediated EPSCs, indicating the presynaptic and postsynaptic actions of CA on neuronal activity. Furthermore, the DL-TBOA infusions could effectively mitigate the diminished GluN2B-LTD and GluN2B-EPSCs and the impairments in behavioral flexibility. Our findings provide the first evidence that CA can exert neurotoxic effects on females and certify that one of the potential mechanisms for neuronal and synaptic dysfunction is the GluN2B-mediated signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glyphosate (Gly) is a broad-spectrum herbicide responsible for the inhibition of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase known to be expressed exclusively in plants and not in animals. For decades Gly has been thought to be ineffective in mammals, including humans, until it was demonstrated that rodents treated with the Gly-based herbicide Roundup showed reduced content of neurotransmitters (e.g., serotonin, dopamine, norepinephrine, and acetylcholine), increased oxidative stress in the brain associated with anxiety and depression-like behaviors and learning and memory deficits. Despite compelling evidence pointing to a neurotoxic effect of Gly, an in-depth functional description of its effects on synaptic transmission is still lacking. To investigate the synaptic alterations dependent on Gly administration we performed whole-cell patch-clamp recordings and immunocytochemistry on mouse primary cultured hippocampal neurons. Our findings reveal that 30 min incubation of Gly at the acceptable daily intake dose severely impaired inhibitory GABAergic synapses. Further analysis pointed out that Gly decreased the number of postsynaptic GABA A receptors and reduced the amplitude of evoked inhibitory postsynaptic currents, the readily releasable pool size available for synchronous release and the quantal size. Finally, a decreased number of release sites has been observed. Consistently, morphological analyses showed that the density of both pre- and post-synaptic inhibitory compartments decorating pyramidal cell dendrites was reduced by Gly. In conclusion, our experiments define for the first time the effects induced by Gly on GABAergic synapses, and reveal that Gly significantly impairs both pre- and postsynaptic mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial or personal interests that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Previous electrophysiology studies show that acute ethanol inhibits firing of orbitofrontal (OFC) cortex neurons while chronic intermittent ethanol (CIE) exposure increases firing accompanied by enhanced ethanol drinking. The acute ethanol inhibition of OFC neuronal firing is mediated by inhibitory glycine receptors and is reduced by expressing a plasma membrane calcium ATPase (PMCA) in OFC astrocytes. In this study, we tested the effects of astrocyte PMCA on CIE-induced increases in excitability and alcohol consumption and the physical interaction between OFC astrocytes and neurons. CIE increased neuronal firing in male mice as compared to Air controls while PMCA itself increased firing in Air control male mice. In contrast, PMCA reduced CIE-mediated hyperexcitability of firing in females. CIE did not affect OFC astrocyte size in control or PMCA male mice but increased astrocyte size in female mice. Similar to spiking, PMCA and CIE both increased the number of GluA1 containing synapses within the vicinity of virally labeled astrocytes in male mice but had differential effects in females. The astrocytic interaction with GluA1 labeled synapses was not affected by CIE treatment in male or female control mice, but there was a treatment-dependent effect of PMCA in male mice. CIE increased alcohol consumption in control but not PMCA male mice and had no effect on drinking in female mice. Lastly, OFC astrocyte PMCA expression had no effect on behavioral measures of locomotion, anxiety, spontaneous alternation, or spatial memory. These findings reveal important sex-dependent differences in the physiological, structural and behavioral actions of OFC astrocytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Studies on memory engram have demonstrated how experience and learning can be allocated at a neuronal level for centuries. Recently emerging evidence narrowed down further to the synaptic connections and their patterned allocation on dendrites. Notably, groups of synapses within a specific range within dendrites known as 'synaptic clusters' have been revealed in association with learning and memory. Previous investigations have shown that a variety of factors mediated by both presynaptic inputs and postsynaptic dendrites contribute to clustering. Here, we review the neural mechanism of synaptic clustering and its correlation with memory. We highlight the recent findings about the clustering of synaptic engrams and memory formation and discuss future directions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In humans, a quantifiable number of cortical synapses appears early in fetal life. In this paper, we present a bridge across different scales of resolution and the distribution of synapses across the transient cytoarchitectonic compartments: marginal zone (MZ), cortical plate (CP), subplate (SP), and in vivo MR images. The tissue of somatosensory cortex (7-26 postconceptional weeks (PCW)) was prepared for electron microscopy, and classified synapses with a determined subpial depth were used for creating histograms matched to the histological sections immunoreacted for synaptic markers and aligned to in vivo MR images (1.5 T) of corresponding fetal ages (maternal indication). Two time periods and laminar patterns of synaptogenesis were identified: an early and midfetal two-compartmental distribution (MZ and SP) and a late fetal three-compartmental distribution (CP synaptogenesis). During both periods, a voluminous, synapse-rich SP was visualized on the in vivo MR. Another novel finding concerns the phase of secondary expansion of the SP (13 PCW), where a quantifiable number of synapses appears in the upper SP. This lamina shows a T2 intermediate signal intensity below the low signal CP. In conclusion, the early fetal appearance of synapses shows early differentiation of putative genetic mechanisms underlying the synthesis, transport and assembly of synaptic proteins. "Pioneering" synapses are likely to play a morphogenetic role in constructing of fundamental circuitry architecture due to interaction between neurons. They underlie spontaneous, evoked, and resting state activity prior to ex utero experience. Synapses can also mediate genetic and environmental triggers, adversely altering the development of cortical circuitry and leading to neurodevelopmental disorders., Competing Interests: Declarations. Conflict of interest: The author have no relevant financial or non-financial interests to disclose. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Ethics Committee of School of Medicine University of Zagreb (19.11.2015./protocol number 380–59-10,106–15-168/314)., (© 2024. The Author(s).)

Background: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer's Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear., Methods: In our study, we included 44 Aβ-negative normal controls (CN) and 76 Aβ-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM., Results: Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores., Conclusion: The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts., Competing Interests: Declarations. Institutional review board statement: The present study was approved by the ethics committee, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China. Informed consent statement: Written informed consent has been obtained from the patients to publish this paper. Conflict of interest: Author Fang Xie is an editor in this journal., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite significant advancements in recent decades, gaining a comprehensive understanding of brain computations remains a significant challenge in neuroscience. Using computational models is crucial for unraveling this complex phenomenon and is equally indispensable for studying neurological disorders. This endeavor has created many neuronal models that capture brain dynamics at various scales and complexities. However, most existing models do not account for the potential influence of glial cells, particularly astrocytes, on neuronal physiology. This gap persists even with the emerging evidence indicating their critical role in regulating neural network activity, plasticity, and even neurological pathologies. To address this gap, some works proposed models that include neuron-glia interactions. Also, while some literature focuses on sophisticated models of neuron-glia interactions that mimic the complexity of physiological phenomena, there are also existing works that propose simplified models of neural-glial ensembles. Building upon these efforts, we aimed to contribute further to the field by proposing a simplified tripartite synapse model that encompasses the presynaptic neuron, postsynaptic neuron, and astrocyte. We defined the tripartite synapse model based on the Adaptive Exponential Integrate-and-Fire neuron model and a simplified scheme of the astrocyte model previously proposed by Postnov. Through our simulations, we demonstrated how astrocytes can influence neuronal firing behavior by sequentially activating and deactivating different pathways within the tripartite synapse. This modulation by astrocytes can shape neuronal behavior and introduce irregularities in the firing patterns of both presynaptic and postsynaptic neurons through the introduction of new pathways and configurations of relevant parameters., Competing Interests: Declarations. Conflict of interest: The authors declare no Conflict of interest in this paper., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Synapses of the neocortex specialized during human evolution to develop over extended timescales, process vast amounts of information and increase connectivity, which is thought to underlie our advanced social and cognitive abilities. These features reflect species-specific regulations of neuron and synapse cell biology. However, despite growing understanding of the human genome and the brain transcriptome at the single-cell level, linking human-specific genetic changes to the specialization of human synapses has remained experimentally challenging. In this review, we describe recent progress in characterizing divergent morphofunctional and developmental properties of human synapses, and we discuss new insights into the underlying molecular mechanisms. We also highlight intersections between evolutionary innovations and disorder-related dysfunctions at the synapse., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Most computational models of neurons assume constant ion concentrations, disregarding the effects of changing ion concentrations on neuronal activity. Among the models that do incorporate ion concentration dynamics, simplifications are often made that sacrifice biophysical consistency, such as neglecting the effects of ionic diffusion on electrical potentials or the effects of electric drift on ion concentrations. A subset of models with ion concentration dynamics, often referred to as electrodiffusive models, account for ion concentration dynamics in a way that ensures a biophysical consistent relationship between ion concentrations, electric charge, and electrical potentials. These models include compartmental single-cell models, geometrically explicit models, and domain-type models, but none that model neuronal network dynamics. To address this gap, we present an electrodiffusive network model with multicompartmental neurons and synaptic connections, which we believe is the first compartmentalized network model to account for intra- and extracellular ion concentration dynamics in a biophysically consistent way. The model comprises an arbitrary number of "units," each divided into three domains representing a neuron, glia, and extracellular space. Each domain is further subdivided into a somatic and dendritic layer. Unlike conventional models which focus primarily on neuronal spiking patterns, our model predicts intra- and extracellular ion concentrations (Na+, K+, Cl-, and Ca2+), electrical potentials, and volume fractions. A unique feature of the model is that it captures ephaptic effects, both electric and ionic. In this paper, we show how this leads to interesting behavior in the network. First, we demonstrate how changing ion concentrations can affect the synaptic strengths. Then, we show how ionic ephaptic coupling can lead to spontaneous firing in neurons that do not receive any synaptic or external input. Lastly, we explore the effects of having glia in the network and demonstrate how a strongly coupled glial syncytium can prevent neuronal depolarization blocks., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sætra, Mori. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Abnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early-life adversity (ELA), with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of ELA, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower. Since the rodent hippocampus undergoes intense synaptic pruning during the second and third weeks of life, we investigated whether microglia are required for the synaptic and behavioral aberrations observed in adolescent LB mice. Indeed, transient ablation of microglia from P13-21 in normally developing mice caused sex-specific behavioral and synaptic abnormalities similar to those observed in adolescent LB mice. Furthermore, chemogenetic activation of microglia during the same period reversed the microglial-mediated phagocytic deficits at P17 and restored normal contextual fear conditioning and synaptic connectivity in adolescent LB male mice. Our data support an additional contribution of astrocytes in the sex-specific effects of LB, with increased expression of the membrane receptor MEGF10 and enhanced synaptic engulfment in hippocampal astrocytes of 17-day-old LB females, but not in LB male littermates. These findings suggest a potential compensatory mechanism that may explain the relative resilience of LB females. Collectively, our study highlights a novel role for glial cells in mediating sex-specific hippocampal deficits in a mouse model of ELA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The size of image volumes in connectomics studies now reaches terabyte and often petabyte scales with a great diversity of appearance due to different sample preparation procedures. However, manual annotation of neuronal structures (e.g., synapses) in these huge image volumes is time-consuming, leading to limited labeled training data often smaller than 0.001% of the large-scale image volumes in application. Methods that can utilize in-domain labeled data and generalize to out-of-domain unlabeled data are in urgent need. Although many domain adaptation approaches are proposed to address such issues in the natural image domain, few of them have been evaluated on connectomics data due to a lack of domain adaptation benchmarks. Therefore, to enable developments of domain adaptive synapse detection methods for large-scale connectomics applications, we annotated 14 image volumes from a biologically diverse set of Megaphragma viggianii brain regions originating from three different whole-brain datasets and organized the WASPSYN challenge at ISBI 2023. The annotations include coordinates of pre-synapses and post-synapses in the 3D space, together with their one-to-many connectivity information. This paper describes the dataset, the tasks, the proposed baseline, the evaluation method, and the results of the challenge. Limitations of the challenge and the impact on neuroscience research are also discussed. The challenge is and will continue to be available at https://codalab.lisn.upsaclay.fr/competitions/9169. Successful algorithms that emerge from our challenge may potentially revolutionize real-world connectomics research and further the cause that aims to unravel the complexity of brain structure and function.

Aging is a multifaceted biological process characterized by progressive molecular and cellular damage accumulation. The brain hippocampus undergoes functional deterioration with age, caused by cellular deficits, decreased synaptic communication, and neuronal death, ultimately leading to memory impairment. One of the factors contributing to this dysfunction is the loss of mitochondrial function. In neurons, mitochondria are categorized into synaptic and non-synaptic pools based on their location. Synaptic mitochondria, situated at the synapses, play a crucial role in maintaining neuronal function and synaptic plasticity, whereas non-synaptic mitochondria are distributed throughout other neuronal compartments, supporting overall cellular metabolism and energy supply. The proper function of synaptic mitochondria is essential for synaptic transmission as they provide the energy required and regulate calcium homeostasis at the communication sites between neurons. Maintaining the structure and functionality of synaptic mitochondria involves intricate processes, including mitochondrial dynamics such as fission, fusion, transport, and quality control mechanisms. These processes ensure that mitochondria remain functional, replace damaged organelles, and sustain cellular homeostasis at synapses. Notably, deficiencies in these mechanisms have been increasingly associated with aging and the onset of age-related neurodegenerative diseases. Synaptic mitochondria from the hippocampus are particularly vulnerable to age-related changes, including alterations in morphology and a decline in functionality, which significantly contribute to decreased synaptic activity during aging. This review comprehensively explores the critical roles that mitochondrial dynamics and quality control mechanisms play in preserving synaptic activity and neuronal function. It emphasizes the emerging evidence linking the deterioration of synaptic mitochondria to the aging process and the development of neurodegenerative diseases, highlighting the importance of these organelles from hippocampal neurons as potential therapeutic targets for mitigating cognitive decline and synaptic degeneration associated with aging. The novelty of this review lies in its focus on the unique vulnerability of hippocampal synaptic mitochondria to aging, underscoring their importance in maintaining brain function across the lifespan., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)