Frontiers in Synaptic Neuroscience最新文献

{"title":"Metabolic regulation of synaptic plasticity in anorexia nervosa.","authors":"Olof Lagerlöf, Qiongxuan Lu, Manish Bhattacharjee, Rashmi Arora, Linkun Han, Jingyu Pan, Sabrina Galizia, Peter Asellus, Erik Ekbäck","doi":"10.3389/fnsyn.2026.1830809","DOIUrl":"https://doi.org/10.3389/fnsyn.2026.1830809","url":null,"abstract":"<p><p>Anorexia nervosa (AN) is increasingly understood as a metabo-psychiatric disorder in which metabolic biology and neural circuit function are intrinsically intertwined. Genetic studies reveal that AN is associated with heritable metabolic traits suggesting that metabolic vulnerability contributes to the disorder. The metabolic profile of AN further shapes brain responses; endocrine signals such as insulin, leptin, ghrelin, and adiponectin elicit atypical neural responses in circuits regulating appetite, reward, interoception, and cognitive control. This altered signaling is accompanied by circuit-specific remodeling, suggesting that the chronic metabolic dysregulation seen in AN affects synaptic plasticity across distributed brain regions. Neural systems that integrate metabolic, emotional, and cognitive information-including hypothalamic, striatal, prefrontal, and limbic circuits-show altered plasticity under starvation. Glucose and insulin modulate excitatory-inhibitory balance and synaptic efficacy, while ketone bodies act as starvation-associated neuromodulators influencing transmitter release and structural plasticity. These and other body-to-brain signals recalibrate network dynamics central to food intake, motivation, and learning. At the molecular level, intracellular metabolic sensors such as AMPK, mTOR, and O-GlcNAc function as transducers that convert nutrient availability into changes in protein synthesis, receptor trafficking, and dendritic spine architecture, providing mechanistic links between metabolic state and synaptic remodeling. Overall, converging evidence supports a model in which AN arises from interactions between metabolic traits and the plastic neural circuits mediating food intake, emotion, and cognition. By clarifying how metabolic signals reshape synaptic ensembles in AN, we present a framework for understanding mechanisms of vulnerability and identify targets capable of restoring adaptive plasticity. This review suggests a trajectory in which treatments jointly address metabolic physiology and brain-based processes of learning, motivation, and affect.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1830809"},"PeriodicalIF":4.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837017","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":"Patterned pre-sensory spontaneous activity drives the structural refinement of developing cochlear ribbon synapses.","authors":"Victoria C Halim, Lukas Hallbrucker, Jan F Ahrend, Cristian Setz, Roos A Voorn, Samira Franke, Vanessa Konrad, Alina Seiler, Tina Pangršič, Stefan Roesler, Christian Vogl","doi":"10.3389/fnsyn.2026.1730181","DOIUrl":"https://doi.org/10.3389/fnsyn.2026.1730181","url":null,"abstract":"<p><strong>Introduction: </strong>In the mammalian cochlea, hearing relies on highly specialized ribbon-type synapses between sensory inner hair cells (IHCs) and postsynaptic spiral ganglion neurons. During early postnatal maturation, structural and functional refinements re-shape synaptic morphology and thereby maximize release efficiency in the run-up to hearing onset. This developmental period is further characterized by the occurrence of pre-sensory spontaneous activity waves, which are essential for the functional maturation of the ascending auditory pathway- yet, their importance for IHC presynaptic structural refinement remains uncertain.</p><p><strong>Methods: </strong>To investigate activity-dependent structural plasticity at cochlear ribbon synapses, we combined genetic, pharmacological, and optogenetic approaches with immunohistochemical and electrophysiological analyses. Moreover, we developed a novel optical stimulation device (OSD) that enables millisecond-precise, long-term and differentially-patterned optogenetic activation of cochlear IHCs under tightly controlled conditions within a standard tissue culture incubator.</p><p><strong>Results: </strong>Using this experimental framework, we show that positive as well as negative activity modulation triggers dynamic and rapidly-inducible homeostatic scaling of ribbon synapse morphology. Moreover, our data indicate that the temporal pattern of the presynaptic activity acts as a fundamental regulatory component of this process.</p><p><strong>Discussion: </strong>Our results suggest that - prior to hearing onset - pre-sensory synaptic activity plays a critical role in shaping cochlear ribbon synapse architecture in the developing auditory system.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1730181"},"PeriodicalIF":4.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13050871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633156","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":"The Freiburg framework for multimodal <i>ex situ</i> assessment of neural plasticity in human cortical tissue.","authors":"Jakob Straehle, Christos Galanis, Lukas Grünewald, Elli-Anna Balta, Tobias D Deller, Ute Häussler, Boris Mizaikoff, Jürgen Beck, Andreas Vlachos","doi":"10.3389/fnsyn.2026.1771781","DOIUrl":"10.3389/fnsyn.2026.1771781","url":null,"abstract":"<p><p>Studying human cortical physiology requires access to viable brain tissue, yet species-specific differences limit the translational value of animal models. To address this, multiple laboratories have developed <i>ex situ</i> approaches for investigating neurosurgical access tissue using electrophysiological, molecular, and imaging techniques. Here, we introduce the Freiburg framework-a structured, multimodal approach that integrates high-resolution electrophysiology, advanced imaging, molecular analyses, and Raman microscopy to assess neuronal and glial function under controlled, near-native conditions. Clinical metadata, including preoperative MRI, together with in-patient controls is systematically incorporated to account for biological variability and to enable human-to-human translational (H2H) comparisons. The framework further enables controlled neuromodulatory and pharmacological interventions, including <i>ex situ</i> repetitive transcranial magnetic stimulation (rTMS). By formalizing an end-to-end experimental pipeline, the Freiburg framework supports systematic investigation of human-specific neurophysiological mechanisms and provides a robust foundation for translational human neuroscience.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1771781"},"PeriodicalIF":4.1,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13033784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147591391","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":"Rhythmic network activity in human brain slices: variability, mechanisms, and translational insights.","authors":"Danqing Yang, Dirk Feldmeyer","doi":"10.3389/fnsyn.2026.1798456","DOIUrl":"10.3389/fnsyn.2026.1798456","url":null,"abstract":"<p><p><i>In vitro</i> maintained human brain slices provide a unique experimental platform for investigating rhythmic neuronal network activity, bridging the gap between animal models and clinical studies. A wide range of spontaneous and induced oscillatory activities has been described in human brain slices. However, their occurrence and characteristics are strongly shaped by methodological determinants spanning tissue origin, slice preparation, recording conditions, and induction strategies. This has been shown to have a profound impact on the reproducibility and interpretation of oscillatory dynamics. This review synthesizes current evidence on rhythmic network activity in acute human brain slices, with a particular emphasis on how methodological determinants interact with intrinsic circuit properties to generate oscillatory dynamics. We discuss how different experimental manipulations influence oscillation frequency, stability, and spatial organization. We further examine the cellular and circuit mechanisms underlying rhythmic activity, highlighting the roles of excitatory-inhibitory balance, synaptic dynamics, neuromodulatory influences, and distinct interneuron populations. Finally, we consider how oscillatory patterns differ across disease contexts, particularly epilepsy and tumor-associated cortex, and discuss the translational value and limitations of human brain slices for linking microcircuit mechanisms to pathological and functional brain states.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1798456"},"PeriodicalIF":4.1,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511486","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":"Increased synaptic turnover in injured cortical axons: exploring the role of SARM1 ablation.","authors":"Ensieh Izadi, William Bennett, Jessica Collins, Aidan Bindoff, Anna King, Alison Canty","doi":"10.3389/fnsyn.2026.1741328","DOIUrl":"https://doi.org/10.3389/fnsyn.2026.1741328","url":null,"abstract":"<p><strong>Introduction: </strong>Programmed axon degeneration significantly affects neural connectivity, however, the underlying mechanisms remain poorly understood, particularly in cortical regions. Sterile Alpha and TIR motif-containing protein 1 (SARM1) is a known regulator of axon degeneration in the peripheral nervous system, but its role in cortical axon plasticity, particularly during injury conditions, remains unclear. This study examined the role of SARM1 in synaptic connectivity and remodelling in the adult sensory-motor cortex under normal physiological conditions and following acute axonal injury.</p><p><strong>Methods: </strong>Adult male Thy1-GFP-M mice (3-12 months) expressing EGFP in excitatory neurons were also either wild-type (WT-GFP) or null for SARM1 (SARM1KO-GFP). Using <i>in vivo</i> multiphoton microscopy, long cortical axon segments (~335 μm ± 140 μm), with <i>terminaux</i> and <i>en passant</i> synaptic boutons in the upper layers of the cortical neuropil, were repeatedly imaged at 48-h intervals to assess axon morphology, synaptic density, and synaptic turnover in the presence and absence of SARM1.</p><p><strong>Results: </strong>Without injury, axon morphology, synaptic density, and turnover were similar between WT and SARM1KO groups, suggesting that SARM1 is not necessary for maintaining baseline cortical synaptic connectivity. Following axotomy by laser lesion, the non-degenerating proximal axon (still connected to the soma) showed significant changes in synaptic plasticity, with an increased rate of loss of synapses.</p><p><strong>Discussion: </strong>Our findings suggest that SARM1 plays no role in the remodelling of synapses in the proximal axon after an acute axonal injury.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1741328"},"PeriodicalIF":4.1,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12969063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147432367","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":"Group I metabotropic glutamate receptors differentially modulate excitatory transmission across interneuron types in the human cortex.","authors":"Joanna Grace Sandle, Gábor Molnár, Martin Tóth, Katalin Ágnes Kocsis, Éva Adrienn Csajbók, Pál Barzó, Karri Lamsa, Gábor Tamás","doi":"10.3389/fnsyn.2026.1766413","DOIUrl":"https://doi.org/10.3389/fnsyn.2026.1766413","url":null,"abstract":"<p><strong>Introduction: </strong>Group I metabotropic glutamate receptors (mGluRs) play a critical role in regulating neuronal excitability, synaptic strength, and cortical network activity. Although their physiological functions and involvement in neurological disorders are well established, direct experimental evidence for their role in human cortical neurons remains limited.</p><p><strong>Methods: </strong>We investigated the effects of group I mGluR activation on excitatory synaptic transmission in the human supragranular cortex using paired whole-cell patch-clamp recordings from synaptically connected pyramidal cells and interneurons in acute slices of human neocortex resected during neurosurgery.</p><p><strong>Results: </strong>Activation of mGluRs with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) altered excitatory synaptic efficacy in an interneuron subtype-dependent manner. Specifically, we observed acute enhancement of excitatory postsynaptic current (EPSC) amplitudes in 54% of fast-spiking interneurons and in 15% of non-fast-spiking interneuron types. Applying the same experimental protocol in slices from Wistar rats resulted in a similar increase in synaptic strength in fast-spiking interneurons. However, paired-pulse ratio analysis showed species-dependent differences, which may reflect distinct contributions of pre- and postsynaptic factors to the observed modulation.</p><p><strong>Discussion: </strong>Together, these results demonstrate that acute modulation of pyramidal cell-fast-spiking interneuron synapses via group I mGluRs is conserved between human and rodent neocortex, while pointing to species-specific underlying mechanisms. Moreover, mGluR-mediated modulation exhibits cell-type specificity in human cortical circuits. Collectively, these findings provide direct functional evidence for group I mGluR-dependent synaptic regulation in the human cortex and highlight important species- and cell-type-specific differences that should be considered when extrapolating rodent data to human cortical physiology and disease mechanisms.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1766413"},"PeriodicalIF":4.1,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325839","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":"Enhanced information processing in the human neocortex: cellular mechanisms and translational perspectives.","authors":"Manuela Tore, Laura Monni, Alessio Di Clemente, Michele Giugliano","doi":"10.3389/fnsyn.2026.1770193","DOIUrl":"https://doi.org/10.3389/fnsyn.2026.1770193","url":null,"abstract":"<p><p>Understanding the sophisticated cognitive abilities of the human brain requires understanding its cellular and synaptic components. While rodent studies provide foundational knowledge, recent research using freshly resected human neocortical and hippocampal tissue has revealed unanticipated distinctive cellular characteristics. These properties, identified through <i>in vitro</i> electrophysiology, anatomical reconstructions, and computational modeling, have profound implications for physiological processes and modulatory responses. Here we highlight and review a selection of key unique features of human neurons. Human layer 2/3 pyramidal cells exhibit exceptionally low specific membrane capacitance and distinctive ion channel kinetics. Moreover, human pyramidal-to-pyramidal connections display species-specific synaptic dynamics, recovering from short-term depression much faster than in rodents. We also highlight that human pyramidal neurons exhibit more elaborate dendritic trees, particularly perisomatic branching, and faster, more stable Action Potentials (AP) dynamics. Interestingly, these features allow higher-bandwidth information transfer, reflecting enhanced computational power. All these cell-level differences directly impact how circuits process information and respond to pharmacological interventions. Increasingly, drugs targeting ion channels or synaptic mechanisms are used but often display different efficacy or kinetics in human neurons compared to rodents, reflecting underlying biophysical disparities. Consequently, leveraging human brain tissue is key as it allows for the identification of human-specific drug targets and a more accurate understanding of disease mechanisms. This review highlights these crucial cellular distinctions and underscores the importance of exploiting resected human brain tissue for advancing central nervous system therapeutics.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1770193"},"PeriodicalIF":4.1,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325842","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":"Spatial characterization of backpropagating action potential-evoked Ca²⁺ signals in human cortical layer 2/3 pyramidal neurons.","authors":"Ildikó Szöts, Martin Tóth, Csongor Ludányi, Pál Barzó, Éva Adrienn Csajbók, Gábor Tamás, Gábor Molnár","doi":"10.3389/fnsyn.2026.1769881","DOIUrl":"https://doi.org/10.3389/fnsyn.2026.1769881","url":null,"abstract":"<p><strong>Introduction: </strong>In pyramidal neurons, backpropagating action potentials (bAPs) activate voltage-gated calcium channels (VGCCs), producing compartment-specific dendritic Ca²⁺ transients. While extensively characterized in rodent models, little is known about the spatial properties and channel-specific contributions of bAP-induced Ca²⁺ signals in human cortical neurons.</p><p><strong>Methods: </strong>We used simultaneous whole-cell patch-clamp recordings and two-photon Ca²⁺ imaging in acute human cortical slices to characterize bAP-evoked Ca²⁺ transients along the apical dendrites of layer 2/3 pyramidal neurons.</p><p><strong>Results: </strong>We found that Ca²⁺ signal amplitudes followed a non-linear spatial profile, increasing proximally and peaking between 50-100 µm from the soma before declining in more distal regions. Oblique dendrites exhibited significantly higher Ca²⁺ amplitudes compared to the primary apical branches. Morphological parameters, such as dendritic diameter, spine density, and branching, were correlated with the spatial profile of Ca²⁺ transients to the peak of the calcium signal profile. Pharmacological blockade of VGCCs revealed that major channel subtypes (L-, N-, R-, and T-type) contribute to dendritic Ca²⁺ influx, with distinct spatial effects. In particular, N-type channel blockade produced the largest attenuation in the medial dendritic segments, while T-type channel inhibition affected all regions.</p><p><strong>Discussion: </strong>These findings highlight spatial heterogeneity and channel-specific contributions to dendritic Ca²⁺ signaling in human neocortical neurons and underscore the influence of dendritic morphology on signal propagation.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1769881"},"PeriodicalIF":4.1,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12929537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147304872","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":"Convergence and divergence of molecular mechanisms in Hebbian and homeostatic plasticity.","authors":"Kira M Feighan, Harshit K Thakare, Stephen D Glasgow, Timothy E Kennedy","doi":"10.3389/fnsyn.2026.1761008","DOIUrl":"https://doi.org/10.3389/fnsyn.2026.1761008","url":null,"abstract":"<p><p>The umbrella of synaptic plasticity includes associative, activity-dependent alterations in synaptic strength that are thought to underlie learning and memory, and negative feedback that stabilizes network activity, termed Hebbian and homeostatic plasticity, respectively. These forms of plasticity respond to activity oppositely, and on different spatial and temporal scales. However, despite these fundamental differences, many similar molecular mechanisms are engaged by each form of plasticity to alter synaptic strength. Here, we review molecular mechanisms involved in homeostatic plasticity and compare their involvement in Hebbian plasticity. We focus on synaptic scaling, long-term potentiation, and long-term depression, which are mediated by regulation of post-synaptic amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-type glutamate receptor (AMPARs) accumulation. Addressing synaptic scaffolding, intracellular signaling, cell-adhesion, and secreted factors, we identify mechanisms that appear to be convergent, differentially engaged, and divergent that uniquely regulate homeostatic scaling. These comparisons identify clear gaps to be addressed by future studies that aim to parse the contributions of Hebbian and homeostatic plasticity to regulate AMPAR function.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1761008"},"PeriodicalIF":4.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12926376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283389","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":"Evolutionary neuroeconomic adaptations of fast-spiking neurons in the human neocortex.","authors":"Viktor Szegedi, Abdennour Douida, Gábor Hutóczki, László Novák, Karri Lamsa","doi":"10.3389/fnsyn.2026.1741452","DOIUrl":"10.3389/fnsyn.2026.1741452","url":null,"abstract":"<p><p><i>Homo sapiens</i> has evolved a large and complex neocortex that underlies advanced cognitive capabilities. Neural computation, however, is inherently energy-intensive, and evolutionary pressures have shaped mechanisms that optimize both computational performance and energy efficiency in the human brain. Fast-spiking interneurons, particularly basket cells, are among the most active neuron types in the neocortex, where they play a key role in coordinating time and space in the activity of neuronal networks, but their high activity levels require high metabolic resources. Because the human neocortex is significantly larger than that of rodents-and contains a higher proportion of inhibitory interneurons relative to pyramidal cells-this expansion may have created evolutionary pressure to reduce the energetic cost of fast-spiking neurons. Compared with rodents, human fast-spiking neurons exhibit adaptations that appear to lower energy expenditure while preserving rapid and precise inhibition. One such adaptation is increased input resistance, which allows both excitation and inhibition to occur with reduced transmembrane ion currents, thereby decreasing the energy required to maintain ionic gradients across the plasma membrane. Since higher input resistance also slows down membrane potential changes, these cells show secondary adaptations that maintain rapid electrical signaling. Additional modifications-such as optimized ion channel composition in soma and axon initial segment, enhanced axon myelination, simplified structure of dendritic tree, and multivesicular synapses-further improve electrical signaling and are likely to reduce metabolic demand, collectively reducing ATP consumption in the neuronal network. By integrating cellular and synaptic perspectives, this review highlights how fast-spiking neurons in the human neocortex have evolved differently from those in rodents to balance energy efficiency while maintaining computational power, providing insight into the metabolic constraints of the human brain.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1741452"},"PeriodicalIF":4.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12855415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105157","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}