Frontiers in Synaptic Neuroscience最新文献

{"title":"The how and why for multiple forms of hippocampal LTP.","authors":"Christine M Gall, Aliza A Le, Gary Lynch","doi":"10.3389/fnsyn.2026.1855059","DOIUrl":"10.3389/fnsyn.2026.1855059","url":null,"abstract":"<p><p>Activity-induced Long-Term Potentiation (LTP)-characterized as it is by rapid induction, synapse specificity, and remarkable persistence-has long been considered a primary substrate for memory encoding. There has however been considerable debate about the cellular mechanisms responsible for producing the potentiated state. It seems that much of the confusion can be traced to an implicit assumption that there is a single form of stable potentiation. However, features of LTP in Schaffer-commissural (SC) input to CA1 and perforant path projections from entorhinal cortex to dentate gyrus (DG), show that different nodes of the hippocampal circuit express different types of LTP and that distinctions can be found even within the same population of synapses. For the SC system, brief theta burst stimulation (TBS) elicits LTP that is expressed by an expansion of the spine, postsynaptic density and associated AMPA receptor pool, and stabilized by reorganization of the actin cytoskeleton. Both sexes employ these mechanisms but females rely on locally synthesized estrogen and synaptic estrogen receptors to set processes in motion whereas males more heavily rely on metabotropic NMDA receptor signaling. Extended theta burst trains, high frequency stimulation (HFS), and spike timing paradigms engage mechanisms of LTP induction that differ from those produced by the minimal TBS. And an even more radical form of potentiation is expressed at lateral perforant path (LPP) connections with the DG. In this case, LTP is triggered postsynaptically but expressed presynaptically by increased transmitter release with an endocannabinoid providing the requisite retrograde messenger. These sex- and region-specific differences in plasticity have meaningful consequences for episodic memory encoding and vulnerability to neurological insults.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1855059"},"PeriodicalIF":6.9,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584135","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":"High-frequency, high-intensity electrical stimulation selectively activates human fast-spiking interneurons.","authors":"Jaeyoung Yoon, Ricardo Silva, Scellig Stone, Hart Lidov, Emily Osterweil, Brielle R Ferguson","doi":"10.3389/fnsyn.2026.1843277","DOIUrl":"10.3389/fnsyn.2026.1843277","url":null,"abstract":"<p><p>Electrical brain stimulation has been used to treat epilepsy with therapeutic success, but without complete understanding of its cellular mechanisms of seizure suppression. Using acute human brain slices obtained from pharmaco-resistant epilepsy patients, we delivered high-frequency, high-intensity extracellular electrical stimulation while recording from neocortical layer 2/3 pyramidal neurons (PNs), fast-spiking interneurons (FSINs), and non-fast-spiking interneurons (nFSINs). Electrical stimulation led to an increasingly selective activation of FSINs at higher stimulation frequencies, which consistently fired with high fidelity throughout prolonged stimulation periods while both PNs and nFSINs were suppressed rapidly. In addition, stimulation caused a long-term rebalancing of synaptic weights through selective and differential depression of synaptic inputs, resulting in an approximately twofold increase in the normalized excitatory-to-inhibitory postsynaptic conductance at FSINs while not affecting PNs, thereby providing support for FSIN activation toward increased inhibitory tone and network stabilization. These stimulation-induced effects were accompanied by only minimal changes in neuronal intrinsic excitability.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1843277"},"PeriodicalIF":6.9,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148420683","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":"Calcium at the crossroads of the immunometabolic signaling and comorbidity in schizophrenia.","authors":"Milica M Borovcanin, Monojit Debnath, Slavica Minic Janicijevic, Ivica Petrovic, Nemanja Muric, Vladimir Janjic","doi":"10.3389/fnsyn.2026.1882307","DOIUrl":"10.3389/fnsyn.2026.1882307","url":null,"abstract":"","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1882307"},"PeriodicalIF":6.9,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13310904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351771","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":"Mechanistic insights into the synaptic damage-repair and regeneration processes in neurodegenerative Alzheimer's disease: phytochemicals as neuroprotective agents.","authors":"Bharti Yadav, Prabhakar Gangwar, Kirti Kumari, Anuradha Yadav, Rashmi Rao, Keshav Kumar, Harkomal Verma, Monisha Dhiman, Anil Kumar Mantha","doi":"10.3389/fnsyn.2026.1835778","DOIUrl":"10.3389/fnsyn.2026.1835778","url":null,"abstract":"<p><p>Synaptic failure is one of the earliest and most significant contributors to the cognitive decline in Alzheimer's disease (AD), preceding extensive neuronal loss. Although amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein characterize the disease, memory impairment primarily results from the gradual deterioration of synaptic communications. This decline is caused by a complex interaction among mitochondrial energy deficits, cytoskeletal instability, disrupted exosomal signaling, and immune-mediated synaptic pruning. Mitochondrial dysfunction, particularly affecting complexes I and IV, leads to reduced ATP production, faulty mitophagy and disrupted calcium (Ca²⁺) homeostasis, placing the synapse under constant metabolic stress. Elevated reactive oxygen species (ROS) further activate stress pathways, including p38 MAPK and JNK, contributing to synaptic protein damage and impaired long-term potentiation (LTP). Furthermore, tau hyperphosphorylation destabilizes the neuronal cytoskeleton, weakening dendritic spine integrity and synaptic connectivity. At the same time, Aβ alters the cargo carried by exosomes, facilitating the spread of pathogenic Aβ and tau species between the neurons and modulating microglial activation and complement-mediated synaptic pruning. Additionally, emerging studies highlight the role of NETosis in exacerbating neuroinflammation and compromising the blood-brain barrier (BBB) integrity, thereby increasing synaptic damage. In contrast, phytochemicals such as resveratrol, ginkgolide B, curcumin, ferulic acid, epigallocatechin gallate (EGCG), and quercetin exert neuroprotection by restoring redox balance, altering exosomal communications, stabilizing cytoskeletal signaling, and reducing neuroinflammation. Moreover, delivery techniques such as nanoparticles and engineered exosomes enhance BBB permeability and enable targeted synaptic intervention. Overall, this review summarizes current mechanistic findings and highlights the potential of phytochemicals as multitarget therapeutic agents for synaptic repair and functional recovery in AD.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1835778"},"PeriodicalIF":6.9,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13294076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345116","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":"NMDA receptors play an important role in postictal potentiation in immature rats.","authors":"Pavel Mares, James L Burchfiel, Hana Kubova","doi":"10.3389/fnsyn.2026.1742164","DOIUrl":"10.3389/fnsyn.2026.1742164","url":null,"abstract":"","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1742164"},"PeriodicalIF":6.9,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13287056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316686","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":"NMDA receptor mediated tonic excitatory currents are elicited by EAAT inhibition on human neocortical pyramidal neurons.","authors":"Béla Márton, Levente Ecsedi, Krisztina Pocsai, Abdennour Douida, Karri Lamsa, Gábor Hutóczki, Álmos Klekner, Balázs Pál","doi":"10.3389/fnsyn.2026.1844197","DOIUrl":"10.3389/fnsyn.2026.1844197","url":null,"abstract":"<p><strong>Introduction: </strong>Ambient glutamate is capable of regulating neural excitability and contributes to several brain pathologies. It is well established by experiments on rodent tissue that extrasynaptic glutamate -mainly regulated by astrocytic glutamate uptake- can elicit both phasic slow inward currents (SICs) and tonic inward currents. These currents are thought to be mediated by overlapping mechanisms and receptors; and exist under physiological conditions. SICs were also found in the human neocortex but the existence of the tonic inward currents and their relationship with SICs have not been demonstrated yet.</p><p><strong>Methods: </strong>We aimed to investigate tonic inward currents and their relation to slow inward currents (SICs) elicited by the inhibition of glutamate transport in the human neocortex. Brain samples removed for accessing the primary brain tumors or metastases were collected from patients with broad age range. Slice electrophysiological approach and post-hoc morphological analysis was used.</p><p><strong>Results: </strong>We found that inhibition of the EAAT transporters by DL-TBOA elicited both SICs and tonic inward currents. The tonic current was only partially reverted by the GluN2B subunit specific NMDA receptor (NMDAR) antagonist ifenprodil, whereas SICs were almost fully eliminated. The amplitude of the current was inversely proportional with the age of the patient and disappeared in elderly over the age of 70. The charge transfer of SICs per minute was directly proportional with the magnitude of the tonic inward current. Omitting magnesium from the recording solution or application of the EAAT positive allosteric modulator GT949 did not elicit any notable tonic current.</p><p><strong>Discussion: </strong>In summary, NMDAR-dependent tonic inward currents are overlapping but partially separable phenomena from SICs. One might hypothesize that the tonic current is only present under excitotoxic conditions and do not determine physiological neuronal excitability in human.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1844197"},"PeriodicalIF":6.9,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13279758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148294615","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":"Suicidality as a potential risk and therapeutic target during widespread GLP-1 receptor agonists use: implications of inflammation.","authors":"Milica M Borovcanin, Ivica Petrovic","doi":"10.3389/fnsyn.2026.1869086","DOIUrl":"10.3389/fnsyn.2026.1869086","url":null,"abstract":"","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1869086"},"PeriodicalIF":6.9,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148294653","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":"Automated ROI detection allows rapid quantification of synaptic activity across tens of thousands of synapses in cell culture.","authors":"John Carl Begley, Harald Prüss, Paul Turko, Camin Dean","doi":"10.3389/fnsyn.2026.1832103","DOIUrl":"10.3389/fnsyn.2026.1832103","url":null,"abstract":"<p><p>Synapses are the basic unit of information transfer between neurons. Their dysfunction is a common trigger of cognitive diseases and disorders. However, high-throughput analysis methods to assess synaptic function and dysfunction are lacking. Calcium imaging in cultured neurons in the absence of Mg²⁺ and presence of TTX allows visualization of NMDAR-dependent spontaneous synaptic calcium transients, which report pre and postsynaptic function. Here, we introduce a high-throughput automated analysis pipeline that combines Suite2p ROI detection and Python scripts to analyze tens of thousands of synapses and quantify changes in presynaptic vesicle fusion rates (frequency), postsynaptic function (amplitude), and the number of functional synapses. We use this pipeline to test known NMDAR agonists (glycine) and antagonists (ketamine, memantine, APV), presynaptic function modulating compounds (PDBu), and encephalitis patient-derived NMDAR auto-antibodies, where our pipeline proved more sensitive in detecting dysfunction at the single-synapse level than other methods. The ability to detect, track, and quantify activity across tens of thousands of synapses and millions of synaptic calcium transients using this pipeline will aid drug discovery of compounds that protect synapse function.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1832103"},"PeriodicalIF":6.9,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13254171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251271","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":"Synaptosomes isolated from cryopreserved MND motor cortex reveal altered calcium handling and reduced complex IV-linked respiration.","authors":"Sean D Morrison, Lotten Ragnarsson, Sarah O Cook, Joseph A Rothnagel, Ernst Wolvetang, Bahaa Al-Mhanawi, Mohammed R Shaker, Thomas Robertson, Peter R Dodd, Peter G Noakes","doi":"10.3389/fnsyn.2026.1760254","DOIUrl":"10.3389/fnsyn.2026.1760254","url":null,"abstract":"<p><p>Motor neuron disease (MND) is marked by progressive neurodegeneration in which presynaptic Ca²⁺-handling and mitochondrial metabolism are thought to be vulnerable, but direct functional studies in human brain are scarce because most material is frozen long-term. Here, we show that synaptosomes isolated from paired fresh and experimentally frozen mouse cortex, and from cryopreserved human motor cortex, retain recognisable synaptosome ultrastructural features, synaptic proteome enrichment, and depolarisation-evoked Ca²⁺-mobilisation. K⁺ and veratridine elicited robust, pharmacologically suppressible Ca²⁺ influx across preparations, and response amplitudes in human samples varied by region but did not correlate with donor age, post-mortem interval (PMI), or years in storage. Synaptosomes from neuropathologically confirmed MND motor cortex and hSOD1^G93A mouse cortex showed significantly greater depolarisation-evoked Ca²⁺ entry than their respective controls, suggesting that increased presynaptic Ca²⁺ influx is shared across our human MND cohort and the hSOD1^G93A mouse model. Using synaptosome preparations from MND and control motor cortices in Seahorse respiratory assays, we found that Complex IV-driven oxygen consumption (TMPD/ascorbate-evoked and azide-sensitive) was reduced in MND synaptosomes, whereas donor-matched free-mitochondrial fractions showed no group difference, supporting a Complex IV defect detectable in the synaptosome-enriched fraction within this cohort. By defining protein-to-OCR relationships for both fractions, we provide practical parameters for applying these assays to archived human cohorts. Together, these data suggest that archived cryopreserved human brain tissues can support informative synaptosome Ca²⁺ and bioenergetic readouts, and that synaptosome-enriched preparations may reveal disease-relevant presynaptic phenotypes in MND that are not evident in donor-matched bulk mitochondrial isolates.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1760254"},"PeriodicalIF":6.9,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13236659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148198748","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":"Experience-dependent critical period for synaptic plasticity in the rat olfactory amygdala.","authors":"Belén Aburto-Ponce, Pedro Fernández-Aburto, Jorge Mpodozis, Juan Bacigalupo, Magdalena Sanhueza","doi":"10.3389/fnsyn.2026.1779075","DOIUrl":"10.3389/fnsyn.2026.1779075","url":null,"abstract":"<p><strong>Introduction: </strong>The amygdala is involved in processing and memory of emotional stimuli. The cortical regions of the amygdala are situated medially to the piriform cortex (PC) and are also considered part of the olfactory system, which may explain why scents can evoke strong emotional responses and trigger vivid memories. Similarly to the PC, the anterior cortical nucleus of the amygdala (ACo) is a three-layered structure receiving direct input from the main olfactory bulb (MOB) through the lateral olfactory tract (LOT), without a thalamic relay. While activity processing, plasticity and behavioral relevance of the PC have been extensively studied, evidence on the functional properties of the olfactory amygdala is scarce. ACo participates in the innate response to aversive stimuli and could be involved in olfactory emotional learning. Primary cortices of different sensory modalities display early periods in which afferent connections are particularly plastic, and this is crucial for network maturation. Here, we studied the plastic properties of LOT-ACo synapses during olfactory system maturation, by assessing long-term potentiation (LTP) induction during the first weeks of life.</p><p><strong>Methods: </strong>We performed field recordings of LOT-ACo synaptic potentials in brain slices from rats of 6 to 35 postnatal days (P6-P35) to assess LTP induction by theta-burst stimulation. To investigate if the developmental regulation of plasticity can be altered by early sensory deprivation, we performed unilateral naris occlusion.</p><p><strong>Results: </strong>We found that LTP was significantly higher between P16-P25 (reaching ~30%) compared to earlier or later stages. Interestingly, LTP was missing around the end of the first postnatal month (P26-35). Furthermore, we demonstrated that LTP induction at one month of age was recovered in both hemispheres in rats that were subjected to unilateral sensory deprivation.</p><p><strong>Discussion: </strong>This result suggests the existence of a critical period for LTP induction in olfactory connections to the amygdala. Therefore, ACo may not only be involved in innate responses to biologically relevant odorants, but could also participate in early experience-dependent associative learning. Moreover, olfactory deprivation could extend the critical period for plasticity, making the system prone to undergo plastic changes at later developmental stages.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":"18 ","pages":"1779075"},"PeriodicalIF":6.9,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13219369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148137848","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}