2026-02-23
Ensieh Izadi, William Bennett, Jessica Collins, Aidan Bindoff, Anna King, Alison Canty
IntroductionProgrammed 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.MethodsAdult 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 in vivo multiphoton microscopy, long cortical axon segments (~335 μm ± 140 μm), with terminaux and en passant 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.ResultsWithout 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.DiscussionOur findings suggest that SARM1 plays no role in the remodelling of synapses in the proximal axon after an acute axonal injury.
DOI: 10.3389/fnsyn.2026.17413282026-02-09
Kira M. Feighan, Harshit K. Thakare, Stephen D. Glasgow, Timothy E. Kennedy
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.
DOI: 10.3389/fnsyn.2026.17610082026-01-16
Viktor Szegedi, Abdennour Douida, Gábor Hutóczki, László Novák, Karri Lamsa
Homo sapiens 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.
DOI: 10.3389/fnsyn.2026.17414522026-01-02
Pinky, Zitin Wali, Neha, Prachi Tiwari, Mohamed El-Tanani, Syed Arman Rabbani, Suhel Parvez
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.
DOI: 10.3389/fnsyn.2025.16763172025-10-15
Agnieszka Pawlak, Jakub Stefanowicz, Zofia Kotkowska, Agata Gabryelska, Marcin Sochal, Filip Napieraj, Magdalena Kotlicka-Antczak, Dominik Strzelecki
BackgroundSynaptic 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.ObjectiveThis 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.MethodsWe 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.ResultsSeveral 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.ConclusionTargeted 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.
DOI: 10.3389/fnsyn.2025.16562322025-10-10
Fleming Francis, Dewan Chettri, Deepak Nair
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.
DOI: 10.3389/fnsyn.2025.16613422025-05-27
Jyotsna Mishra, Kyle Bevers, Keguo Li, Armaan Zare, James S. Heisner, Ailing Tong, Wai-Meng Kwok, David F. Stowe, Amadou K. S. Camara
Mitochondria regulate intracellular calcium ion (Ca2+) signaling by a fine-tuned process of mitochondrial matrix (m) Ca2+ influx, mCa2+ buffering (sequestration) and mCa2+ release (Ca2+ efflux). This process is critically important in the neurosynaptic terminal, where there is a simultaneous high demand for ATP utilization, cytosolic (c) Ca2+ regulation, and maintenance of ionic gradients across the cell membrane. Brain synaptic and non-synaptic mitochondria display marked differences in Ca2+ retention capacity. We hypothesized that mitochondrial Ca2+ handling in these two mitochondrial populations is determined by the net effects of Ca2+ uptake, buffering or efflux with increasing CaCl2 boluses. We found first that synaptic mitochondria have a more coupled respiration than non-synaptic mitochondria; this may correlate with the higher local energy demand in synapses to support neurotransmission. When both mitochondrial fractions were exposed to increasing mCa2+ loads we observed decreased mCa2+ sequestration in synaptic mitochondria as assessed by a significant increase in the steady-state free extra matrix Ca2+ (ss[Ca2+]e) compared to non-synaptic mitochondria. Since, non-synaptic mitochondria displayed a significantly reduced ss[Ca2+]e, this suggested a larger mCa2+ buffering capacity to maintain [Ca2+]m with increasing mCa2+ loads. There were no differences in the magnitude of the transient depolarizations and repolarizations of the membrane potential (ΔΨm) and both fractions exhibited similar gradual depolarization of the baseline ΔΨm during additional CaCl2 boluses. Adding the mitochondrial Na+/Ca2+ exchanger (mNCE) inhibitor CGP37157 to the mitochondrial suspensions unmasked the mCa2+ sequestration and concomitantly lowered ss[Ca2+]e in synaptic vs. non-synaptic mitochondria. Adding complex V inhibitor oligomycin plus ADP (OMN + ADP) bolstered the matrix Ca2+ buffering capacity in synaptic mitochondria, as did Cyclosporin A (CsA), in non-synaptic. Our results display distinct differences in regulation of the free [Ca2+]m to prevent collapse of ΔΨm during mCa2+ overload in the two populations of mitochondria. Synaptic mitochondria appear to rely mainly on mCa2+ efflux via mNCE, while non-synaptic mitochondria rely mainly on Pi-dependent mCa2+ sequestration. The functional implications of differential mCa2+ handling at neuronal synapses may be adaptations to cope with the higher metabolic activity and larger mCa2+ transients at synaptosomes, reflecting a distinct role they play in brain function.
DOI: 10.3389/fnsyn.2025.1562065