Frontiers in Synaptic Neuroscience最新文献

{"title":"Aging and Alzheimer's: the critical role of mitochondrial dysfunction and synaptic alterations.","authors":"Pinky, Zitin Wali, Neha, Prachi Tiwari, Mohamed El-Tanani, Syed Arman Rabbani, Suhel Parvez","doi":"10.3389/fnsyn.2025.1676317","DOIUrl":"10.3389/fnsyn.2025.1676317","url":null,"abstract":"<p><p>Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic dysfunction, and mitochondrial impairment. Despite multiple therapeutic strategies, currently available treatments only provide symptomatic relief without halting disease progression. Emerging evidence implicates mitochondrial dysfunction-including oxidative stress, impaired calcium signaling, mitophagy deficits, disrupted proteostasis, and electron transport chain abnormalities, as central to AD pathogenesis. These dysfunctions contribute to synaptic degeneration, increased reactive oxygen species, and neuronal death. This review consolidates current knowledge on the mechanistic pathways of mitochondrial impairment in AD and their downstream effects on neuronal health. We also explore the therapeutic potential of multitarget approaches, including agents targeting Aβ and tau pathology, oxidative stress mitigation, mitochondrial quality control, and synaptic restoration. By integrating evidence from recent preclinical and clinical studies, this work highlights mitochondrial homeostasis as a promising frontier for disease-modifying therapies in AD.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1676317"},"PeriodicalIF":4.1,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12808448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic transmission in supragranular layers of the human cortex - comparative review of structure, function, and plasticity.","authors":"Amelie Eichler, Pia Kruse, Charlotte Schob, Maximilian Lenz","doi":"10.3389/fnsyn.2025.1724377","DOIUrl":"10.3389/fnsyn.2025.1724377","url":null,"abstract":"<p><p>Synapses are the highly specialized connection sites between neurons enabling the establishment of complex neuronal networks. As highly plastic structures, synapses collocate both the transmission and storage of information, which is an essential prerequisite for learning and memory. Since synaptic deficits are associated with degenerative and neuropsychiatric diseases, it is essential to understand the mechanisms of synaptic plasticity. Throughout evolution, the human brain has developed distinct characteristics, such as supragranular expansion and enhanced long-range connectivity, suggesting an evolutionary specialization of synapses. Recent collaborative research, employing slice preparations obtained from neurosurgical resections of the human neocortex, has significantly advanced our understanding of the unique structural and functional properties of the human neocortex. This review investigates findings derived from diverse experimental methodologies, highlighting specific synaptic features. Focusing on synapses in supragranular layers, we discuss the distinctive synaptic structure, function, and mechanisms of plasticity that contribute to the unique circuitry of the adult human brain. Additionally, we outline emerging directions of research aimed at further elucidating the functionality of human cortical networks.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1724377"},"PeriodicalIF":4.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From microelectrode arrays to all-optical and multimodal neural interfaces: emerging platforms for spatiotemporal interrogation of <i>in vitro</i> neural circuits.","authors":"Song Wang, Sarah Gordon, Chris French, Ranjith R Unnithan, Dechuan Sun","doi":"10.3389/fnsyn.2025.1732955","DOIUrl":"10.3389/fnsyn.2025.1732955","url":null,"abstract":"<p><p>Understanding how synaptic interactions lead to circuit dynamics for neural computation requires experimental tools that can both observe and perturb neuronal activity across spatial and temporal scales. Microelectrode arrays (MEAs) provide scalable access to population spiking activity, yet they lack the spatial resolution and molecular specificity to precisely dissect synaptic mechanisms. In contrast, recent advances in optogenetic actuators, genetically encoded calcium and voltage indicators, and patterned photostimulation have transformed <i>in vitro</i> research, enabling all-optical interrogation of synaptic plasticity, functional connectivity, and emergent network dynamics. Further progress in transparent MEAs and hybrid optical-electrical systems has bridged the divide between electrophysiology and optical control, allowing simultaneous, bidirectional interaction with biological neural networks (BNNs) and real-time feedback modulation of activity patterns. Together, these multimodal <i>in vitro</i> platforms provide unprecedented experimental access to how local interactions shape global network behavior. Beyond technical integration, they establish a foundation for studying biological computation, linking mechanistic understanding of synaptic processes with their computational outcomes. This mini-review summarizes the progression from conventional MEA-based electrophysiology, through all-optical interrogation, to integrated multimodal frameworks that unite the strengths of both modalities.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1732955"},"PeriodicalIF":4.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12722870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABA_B receptors negatively modulate excitatory plasticity at the mossy fiber synapse onto parvalbumin-expressing basket and axo-axonic cells in the dentate gyrus.","authors":"Rita M Loureiro, Sam A Booker, Akos Kulik, Imre Vida","doi":"10.3389/fnsyn.2025.1656759","DOIUrl":"10.3389/fnsyn.2025.1656759","url":null,"abstract":"<p><strong>Introduction: </strong>GABA_B receptors (GABA_BRs) are important modulators of neuronal excitability, synaptic transmission and plasticity in principal cells (PCs). While at the cellular level they can inhibit synaptic transmission directly, at the network level, due to a net disinhibitory effect, they promote plasticity in PCs. However, their effect on plasticity in GABAergic interneurons (INs) is less well-understood.</p><p><strong>Methods: </strong>In this study, we have combined quantitative immunoelectron microscopy and <i>ex vivo</i> whole-cell recordings to investigate the surface expression of GABA_BRs and their modulation of synaptic plasticity at mossy fiber (MF) inputs onto parvalbumin-expressing interneurons (PV-INs) in the rat dentate gyrus (DG).</p><p><strong>Results: </strong>Immunoelectron microscopy confirmed the expression of the GABA_BRs and their effector channel Kir3.1 on PV-IN dendritic shafts. Theta-burst extracellular stimulation of MFs resulted in robust long-term potentiation (LTP) in basket cells (BCs) and axo-axonic cells (AACs), the two main types of DG PV-INs. LTP in both types was strongly reduced, but not abolished, by the GABA_BR agonist baclofen.</p><p><strong>Discussion/conclusion: </strong>Finally, pre-application of SCH-23390, a blocker of Kir3 channels, occluded the inhibitory effect of baclofen on LTP. These results demonstrate that postsynaptic GABA_BRs negatively regulate synaptic plasticity at MF synapses onto DG perisomatic-inhibitory PV-INs via Kir3 channels.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1656759"},"PeriodicalIF":4.1,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12669201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opposite serotonergic modulation of sharp waves in the dorsal and ventral hippocampus.","authors":"Charalampos L Kandilakis, Costas Papatheodoropoulos","doi":"10.3389/fnsyn.2025.1701349","DOIUrl":"10.3389/fnsyn.2025.1701349","url":null,"abstract":"<p><p>Serotonin plays a crucial role in regulating hippocampal network dynamics, however, its effects on sharp wave-ripples (SPWs), a pattern fundamental for memory consolidation and emotional processing, remain incompletely understood, particularly along the dorsoventral axis. Using hippocampal slices from adult rats, we compared serotonergic modulation of SPWs and associated multiunit activity (MUA) in dorsal and ventral CA1 regions. Serotonin (1-100 μM) was applied to evaluate dose dependent and region-specific effects on SPW amplitude, duration, frequency, and neuronal firing. We found that serotonin reduces SPW amplitude in both hippocampal segments, decreases the rate of SPW occurrence in the dorsal hippocampus, and increases the rate of SPW occurrence in the ventral hippocampus, but only at relatively low concentrations. The suppressive effect on SPW amplitude is accompanied by a reduction in firing frequency during SPWs in both regions, whereas the enhancing effect of low serotonin concentrations on SPW rate in the ventral hippocampus is associated with an excitatory action on basal neuronal activity. These results reveal a region-specific, and dose-dependent serotonergic modulation of SPWs, reflecting distinct excitatory/inhibitory balances and receptor subtype distributions along the hippocampal axis. Functionally, serotonergic suppression of dorsal SPWs may regulate cognitive processes, whereas bidirectional modulation in the ventral hippocampus may fine-tune affective and stress-related responses. Our findings highlight dorsoventral specialization of serotonergic control over hippocampal network patterns, providing insights into the mechanisms of dorsoventral hippocampal specialization and the symptom heterogeneity of neuropsychiatric disorders involving serotonergic dysfunction.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1701349"},"PeriodicalIF":4.1,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12626976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is it possible to prevent excessive synaptic pruning in schizophrenia? Possibilities and limitations.","authors":"Agnieszka Pawlak, Jakub Stefanowicz, Zofia Kotkowska, Agata Gabryelska, Marcin Sochal, Filip Napieraj, Magdalena Kotlicka-Antczak, Dominik Strzelecki","doi":"10.3389/fnsyn.2025.1656232","DOIUrl":"10.3389/fnsyn.2025.1656232","url":null,"abstract":"<p><strong>Background: </strong>Synaptic pruning is a critical neurodevelopmental process that eliminates redundant or weak synaptic connections to optimize brain circuitry. In schizophrenia, converging evidence from imaging, genetic, and postmortem studies suggests that this process is pathologically accelerated, particularly in the prefrontal cortex during adolescence. The resulting reduction in synaptic density has been implicated in disrupted neural connectivity observed in psychosis, with the onset of cognitive impairment and negative symptoms.</p><p><strong>Objective: </strong>This review explores whether modulating aberrant synaptic pruning could serve as a preventive or early intervention strategy for schizophrenia. We analyze domains with emerging therapeutic relevance: tetracycline antibiotics, the complement system and C4 gene, kynurenine pathway modulation, epigenetic therapies, neuroprotective strategies (e.g., BDNF, NF-κB, progranulin), genetic and transcriptional regulators of pruning, and other new, mostly hypothetical, options. We also discuss the limitations of the impact on pruning.</p><p><strong>Methods: </strong>We conducted a structured review of the mechanisms involved in pruning, as well as clinical trials, preclinical studies, and mechanistic models that investigate molecular targets influencing synaptic pruning in schizophrenia.</p><p><strong>Results: </strong>Several molecular pathways have been implicated in abnormal synaptic pruning in schizophrenia, including complement C4A overexpression, kynurenine pathway imbalance (KYNA/QUIN), and dysregulation of microglial and transcriptional modulators such as MEF2C and TCF4. While retrospective studies suggest minocycline or doxycycline may reduce psychosis risk, randomized trials remain inconclusive. Emerging interventions, including LSD1 inhibitors, BDNF/progranulin enhancers, and lifestyle-based epigenetic modulation, show promise but require further validation in clinical settings. We also discuss the limitations of these methods, including safety considerations.</p><p><strong>Conclusion: </strong>Targeted modulation of synaptic pruning represents a promising but complex therapeutic strategy. The timing, specificity, and reversibility of interventions are crucial to avoid disrupting essential neurodevelopment. Future efforts should focus on identifying biomarkers for patient stratification and validating preventive strategies in high-risk populations.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1656232"},"PeriodicalIF":4.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12568506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPA receptors in the evolving synapse: structure, function, and disease implications.","authors":"Fleming Francis, Dewan Chettri, Deepak Nair","doi":"10.3389/fnsyn.2025.1661342","DOIUrl":"10.3389/fnsyn.2025.1661342","url":null,"abstract":"<p><p>Synapses, once considered static conduits for neuronal signals, are now recognized as dynamic, multifunctional structures critical to brain function, plasticity, and disease. This evolving understanding has highlighted the tripartite nature of synapses, including pre-synaptic terminals, post-synaptic compartments, and regulatory glial elements. Among excitatory synapses, glutamatergic transmission dominates, with AMPA receptors (AMPARs) playing a central role in fast synaptic signaling. AMPARs are tetrameric, ligand-gated ion channels that mediate rapid depolarization and are tightly regulated by subunit composition, trafficking, and interactions with scaffolding and signaling proteins. Their activity-dependent modulation underpins key processes such as long-term potentiation and depression, central to learning and memory. Importantly, dysfunctions in AMPAR expression, localization, or signaling are increasingly linked to neurological and psychiatric disorders including autism spectrum disorders, epilepsy, schizophrenia, and Alzheimer's disease. This review discusses AMPAR biology in the context of synaptic organization, highlighting recent advances and ongoing challenges in understanding their roles in health and disease.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1661342"},"PeriodicalIF":4.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12551409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145372541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the singularity of human neurons: keep calm and carry on.","authors":"Baptiste Libé-Philippot","doi":"10.3389/fnsyn.2025.1672646","DOIUrl":"10.3389/fnsyn.2025.1672646","url":null,"abstract":"<p><p>The human brain's increased cognitive abilities are underpinned by evolutionary adaptations at the molecular, cellular, and circuit levels of neural structures. This perspective explores how protracted neuronal development and divergent cell intrinsic neuronal properties, including neuronal excitability, contribute to human neurobiological singularity. Those cellular aspects rely on molecular evolutionary innovations, including evolution of gene regulation and gene duplications that play critical roles in prolonging synaptogenesis and reducing neuronal excitability. These molecular evolutionary innovations are shown to interact with core neurodevelopmental molecular pathways linked to neurodevelopmental disorders. Furthermore, complementary multimodal and multiscale approaches offer promising platforms to study these processes and develop species-relevant therapeutic strategies. They include <i>ex vivo</i> acute brain slices and organotypic cultures which offer emerging tools for understanding human species-specificities and neural disorders.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1672646"},"PeriodicalIF":4.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12528094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKMζ drives spatial memory reconsolidation but not maintenance.","authors":"João Rodrigo de Oliveira, Janine I Rossato, Johseph P G Souza, Rodrigo Orvate, Livia Carneiro, Ana Luizi Baracho, Martín Cammarota","doi":"10.3389/fnsyn.2025.1638371","DOIUrl":"10.3389/fnsyn.2025.1638371","url":null,"abstract":"<p><p>Non-reinforced reactivation destabilizes spatial memory in the Morris water maze (MWM), triggering reconsolidation, a protein synthesis-dependent process that restabilizes reactivated memories. PKMζ is a constitutively active, atypical PKC isoform implicated in memory storage. However, the potential involvement of this kinase in spatial memory reconsolidation remains unexplored. We found that intra-dorsal CA1 infusion of the PKMζ inhibitor myristoylated ζ-inhibitory peptide (ZIP), but not its inactive scrambled analog scZIP, following non-reinforced spatial memory reactivation in the MWM, induced time-dependent, long-lasting amnesia in adult male Wistar rats. This effect was replicated by silencing PKMζ mRNA translation with phosphorothioated antisense oligonucleotides, but not by inhibiting the related PKCι/<i>λ</i> with ICAP, and was prevented by disrupting hippocampal GluN2B-NMDAR signaling with RO25-6981, proteasome activity with clasto-lactacystin β-lactone, and AMPAR endocytosis with dynasore hydrate. ZIP had no effect on retention when given without reactivation or after reinforced reactivation. These findings suggest hippocampal PKMζ is necessary for spatial memory reconsolidation in the MWM, but not for its passive maintenance.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1638371"},"PeriodicalIF":4.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morphological variability may limit single-cell specificity to electric field stimulation.","authors":"Daniel Trotter, Aref Pariz, Axel Hutt, Jérémie Lefebvre","doi":"10.3389/fnsyn.2025.1621352","DOIUrl":"10.3389/fnsyn.2025.1621352","url":null,"abstract":"<p><strong>Introduction: </strong>Non-invasive brain stimulation techniques, widely used to manipulate neural excitability and behavior, are well studied at the meso- and macroscopic scales. However, less is known about their specificity at the level of individual cells.</p><p><strong>Methods: </strong>Models based on real pyramidal and parvalbumin neuron morphologies created by the Allen Institute for Brain Science were characterized using metrics we devised to quantify various aspects of cellular morphology, ranging from whole cell attributes to net compartment length, branching, diameter and orientation. The models were simulated to quantify the single-cell variability and evoked response susceptibility to uniform electric fields.</p><p><strong>Results and discussion: </strong>No physical traits yielded layer- or cell-type-specific responses passing statistical significance tests. While uniform electric fields reliably modulated somatic, dendritic and axonal compartments, and subtype-specific responses were observed, specificity was blurred by the variability in cellular morphology. These null results suggest morphology alone may not account for the reported subtype specificity to electric field stimulation, and question the extent to which non-invasive techniques can control specific components of neural circuitry.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"17 ","pages":"1621352"},"PeriodicalIF":4.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}