Neuroscience Letters最新文献

{"title":"Human microglia express anti-inflammatory ISG15 in response to Neisseria meningitidis","authors":"Andrew M. Dunphy,&nbsp;Krishna Majithia,&nbsp;Quinton A. Krueger,&nbsp;M. Brittany Johnson,&nbsp;Ian Marriott","doi":"10.1016/j.neulet.2026.138543","DOIUrl":"10.1016/j.neulet.2026.138543","url":null,"abstract":"<div><div>Glial cells respond to the presence of bacteria by producing inflammatory mediators but these responses can result in damage to the central nervous system (CNS). However, glia can also produce immunosuppressive mediators that can serve to mitigate such effects. Here, we demonstrate that human microglial cells and, to a lesser extent, primary human astrocytes, can express and secrete interferon stimulated gene 15 (ISG15) in response to a clinically relevant CNS pathogen, <em>Neisseria meningitidis,</em> and ligands for Toll-like receptor 4 (TLR4) that include lipopolysaccharide and lipooligosaccharide derived from <em>N. meningitidis</em>. Exogenous ISG15 failed to elicit human neutrophil-like cell migration and induce or augment their inflammatory responses. Similarly, recombinant ISG15 application did not elicit inflammatory cytokine or chemokine production by either human microglial cells or astrocytes, and did not augment their responses to TLR stimulation or <em>N. meningitidis</em> infection. Rather, ISG15 treatment limited <em>N. meningitidis</em>-induced NF-κB activation and associated inflammatory cytokine production by these cells, perhaps via a non-canonical TLR-mediated pathway. These observations may be indictive of a novel negative feedback loop whereby the recognition of bacterial motifs precipitates ISG15 expression by resident microglia that subsequently mitigates further neuroinflammatory responses.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"875 ","pages":"Article 138543"},"PeriodicalIF":2.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146191069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural basis of cognitive-perceptual and negative affect: the linking role of ventral anterior insula connectivity","authors":"Liyun Han ,&nbsp;Xianrui Li ,&nbsp;Yawen Zhang ,&nbsp;Jinbao Chen ,&nbsp;Jing Zhang ,&nbsp;Jiang Qiu ,&nbsp;Min Chen","doi":"10.1016/j.neulet.2026.138537","DOIUrl":"10.1016/j.neulet.2026.138537","url":null,"abstract":"<div><h3>Background</h3><div>Schizotypal personality (SP) is characterized by cognitive-perceptual disturbances, interpersonal difficulties, and disorganized behavior. We examined associations between SP traits and affect, and insula-centered neural mechanisms underlying this link.</div></div><div><h3>Methods</h3><div>One hundred sixty-one university students completed the Schizotypal Personality Questionnaire–Brief and the Positive and Negative Affect Schedule and underwent resting-state fMRI. Seed-based whole-brain functional connectivity (FC) analyses used bilateral ventral anterior, dorsal anterior, and posterior insula seeds. Pearson correlations and mediation analyses tested associations among SP traits, negative affect, and FC.</div></div><div><h3>Results</h3><div>Cognitive–perceptual traits correlated positively with negative affect (<em>r</em> = 0.36, <em>p</em> &lt; 0.001). FC between the right inferior parietal lobule (IPL.R) and the left ventral anterior insula (vAI.L) was positively correlated with cognitive–perceptual traits (<em>r</em> = 0.33, <em>p</em> &lt; 0.001), whereas FC between the right cerebellar Crus I and the vAI.L was negatively correlated (<em>r</em> = −0.37, <em>p</em> &lt; 0.001). FC between the right ventral anterior insula (vAI.R) and the Left Calcarine Gyrus (CAL.L) was also negative (<em>r</em> = −0.30, <em>p</em> &lt; 0.001). vAI.L–IPL.R FC partially mediated the cognitive–perceptual traits–negative affect association (indirect effect = 0.1883, 95% bootstrap CI [0.0246, 0.4022]).</div></div><div><h3>Conclusion</h3><div>vAI.L–IPL.R FC partially accounts for the link between cognitive–perceptual traits and negative affect, highlighting a potential neural pathway underlying affective vulnerability in SP.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"875 ","pages":"Article 138537"},"PeriodicalIF":2.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulatory effects of GLT-1 enhancer, MC-100093, on neuroinflammatory factors in mesocorticolimbic brain regions of female P rats exposed chronically to ethanol","authors":"Khokon Kanti Bhowmik ,&nbsp;Ahmed Alotaibi ,&nbsp;Magid Abou-Gharbia ,&nbsp;Wayne Childers ,&nbsp;Youssef Sari","doi":"10.1016/j.neulet.2026.138525","DOIUrl":"10.1016/j.neulet.2026.138525","url":null,"abstract":"<div><div>Chronic ethanol intake increases extracellular glutamate concentrations in important reward-related brain regions, including the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), ultimately resulting in oxidative stress and inflammation. Recent studies from our laboratory demonstrated that MC-100093, a synthetic beta-lactam lacking antibacterial properties and functioning as a GLT-1 modulator, decreased ethanol consumption. This study examined the impact of the GLT-1 modulator, MC-100093, on chronic ethanol consumption and neuroinflammation in specific subregions of the NAc (core and shell) and mPFC (Prelimbic, PL; and Infralimbic, IL) in female alcohol preferring rats in a dose-dependent manner. MC-100093 treatment decreased ethanol consumption at both doses (100 and 150 mg/kg, i.p.) following a five-week drinking paradigm. MC-100093 attenuated ethanol-induced increase of the pro-inflammatory cytokines HMGβ-1 and TNF-α expression across all investigated mesocorticolimbic brain regions. Moreover, MC-100093 treatment attenuated the ethanol-induced increase of RAGE expression in these brain regions at both doses. MC-100093 treatment decreased ethanol consumption, and this behavioral outcome correlated with a reduction in pro-inflammatory markers, indicating that MC-100093 may serve as a potential agent for mitigating the effects of chronic ethanol exposure associated with inflammation.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"875 ","pages":"Article 138525"},"PeriodicalIF":2.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of calcium currents and their contributions to firing behaviour of primary motoneurons in developing zebrafish","authors":"Stephanie F. Gaudreau,&nbsp;Tuan V. Bui","doi":"10.1016/j.neulet.2026.138522","DOIUrl":"10.1016/j.neulet.2026.138522","url":null,"abstract":"<div><div>Calcium currents in vertebrate motoneurons undergo developmental changes as motoneurons mature and develop specialized functions. The rapid development of zebrafish presents a unique opportunity to link changes in calcium currents of motoneurons to changes in the rapid and stereotyped motor maturation of zebrafish. As swimming matures from crude, large amplitude body bends to refined, low amplitude tailbeats, the involvement of the primary motoneurons that innervate fast muscle becomes less prevalent. During this time, primary motoneuron innervation, dendritic arborization, and firing properties become refined. In this study, we aimed to characterize the presence and influence on firing behaviour of low-voltage and high-voltage activated calcium currents in primary motoneurons during early development, when primary motoneurons undergo functional maturation. Our whole-cell patch-clamp electrophysiology data in zebrafish aged 2 to 5 days post-fertilization (dpf) reveal unique characteristics of calcium currents in zebrafish primary motoneurons, such as the influence of L-type and N-type calcium currents on the regulation of repetitive firing at 3 and 5 dpf, the emergence of P/Q-type calcium currents that regulate repetitive firing as of 4 dpf, and the absence of post-inhibitory rebounds characteristic of T-type calcium currents. These findings highlight how precise changes in properties of ion currents can shape neuronal function during development.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"875 ","pages":"Article 138522"},"PeriodicalIF":2.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The distribution map of α4 and α7 subunits of nAch receptors in the olfactory bulb of male rat neonates born to STZ-induced hyperglycemia model mothers","authors":"Raheleh Baradaran ,&nbsp;Nasim Alipour ,&nbsp;Fatemeh Rahimi Anbarkeh ,&nbsp;Nasibeh Ghandy","doi":"10.1016/j.neulet.2026.138519","DOIUrl":"10.1016/j.neulet.2026.138519","url":null,"abstract":"<div><h3>Background</h3><div>Alpha4 and alpha7 nicotinic acetylcholine receptors (nAChRs) are critical for neuronal survival and are highly expressed in the rat olfactory bulb (OB). Gestational diabetes mellitus (GDM) affects the central nervous system, including the OB. This study investigates the effects of maternal diabetes on the distribution of alpha4 and alpha7 nAChR subunits in the OB of male rat neonates.</div></div><div><h3>Methods</h3><div>Timed-pregnant female Wistar rats were randomly assigned to three groups: Control (no intervention), Stz (streptozotocin, 45 mg/kg, i.p.), and Stz + Ins (streptozotocin, 45 mg/kg, i.p., plus 4–6 units of Neutral Protamine Hagedorn insulin, subcutaneous daily). One week after STZ-induced hyperglycemia confirmation, females were mated with non-diabetic males, with vaginal plaque observation marking gestation day 1. After natural childbirth, Male pups were divided into two age subgroups: postnatal day 7 (P7, n = 4) and postnatal day 14 (P14, n = 4). Brains were extracted for immunohistochemical analysis of alpha4 and alpha7 nAChR expression and dark neuron counts.</div></div><div><h3>Results</h3><div>The optical density (OD) of alpha4 and alpha7 nAChRs in the Stz group was significantly lower than in the Control group across all OB layers at P7 and P14. Conversely, the Stz + Ins group exhibited significantly higher OD compared to the Stz group. Dark neuron counts were significantly elevated in the Stz group compared to the Control and Stz + Ins groups, particularly in the mitral cell layer.</div></div><div><h3>Conclusion</h3><div>Maternal hyperglycemia reduces nAChR expression and increases dark neuron populations in the OB of neonatal rats, potentially contributing to olfactory dysfunction. Insulin treatment mitigates these adverse effects.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"875 ","pages":"Article 138519"},"PeriodicalIF":2.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered brain glucose metabolism in nicotine use but not in hazardous alcohol consumption or problem gambling of healthy men","authors":"Seunghyeon Shin ,&nbsp;Keunyoung Kim ,&nbsp;Jihyun Kim ,&nbsp;Hyun–Yeol Nam ,&nbsp;Ju Won Seok ,&nbsp;Kyoungjune Pak","doi":"10.1016/j.neulet.2026.138523","DOIUrl":"10.1016/j.neulet.2026.138523","url":null,"abstract":"<div><div>We aimed to determine whether chronic nicotine use, alcohol consumption, and gambling alters brain glucose metabolism. We retrospectively analyzed data from 131 healthy men who participated in health check-ups at Samsung Changwon Hospital Health Promotion Center during 2013 (baseline) and 2018 (follow-up). The health checks included a brain ¹⁸F-fluorodeoxyglucose positron emission tomography (PET), a questionnaire of tobacco use, the Alcohol Use Disorders Identification Test (AUDIT; Korean version), and the Problem Gambling Severity Index (PGSI). From brain PET scans, the mean uptake in regions-of-interest was scaled to the mean global cortical uptake by each individual, defining the standardized uptake value ratio. We established a model for tobacco use, AUDIT, and PGSI with regional SUVR as a dependent variable and tobacco use, AUDIT, and PGSI as predictors adjusted for age using Bayesian hierarchical modelling. All data were analyzed using R (The R Foundation for Statistical Computing). This study included 131 healthy males (mean age at baseline and follow-up: 43.0 ± 3.4, 48.1 ± 3.3 years, respectively). Tobacco use was negatively associated with glucose metabolism in the caudate, thalamus, cingulate, and frontal lobe, and positively associated with the cerebellum, whereas AUDIT or PGSI were not associated with regional glucose metabolism. In conclusion, tobacco use was associated with altered brain glucose metabolism in the caudate, thalamus, cingulate, frontal lobe, and the cerebellum. However, neither hazardous alcohol consumption, nor problem gambling showed any association with brain glucose metabolism. Our findings might provide new insights into the neural mechanisms of chronic nicotine use.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"875 ","pages":"Article 138523"},"PeriodicalIF":2.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine-1-phosphate attenuates seizures and cognitive deficits, associated with reduced hippocampal IL-1β in a PTZ-induced epilepsy model","authors":"Kai Luo ,&nbsp;Weiwen Zeng ,&nbsp;Qing Chen ,&nbsp;Zhijian Ma ,&nbsp;Shixiong Huang ,&nbsp;Xinyu Ben","doi":"10.1016/j.neulet.2026.138527","DOIUrl":"10.1016/j.neulet.2026.138527","url":null,"abstract":"<div><h3>Background and aim</h3><div>Epilepsy is a prevalent neurological disorder frequently accompanied by cognitive impairments and neuronal damage. Neuroinflammation—particularly mediated by interleukin-1β (IL-1β)—plays a critical role in epileptogenesis. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, has been implicated in neuroprotection and anti-inflammatory signaling; however, its role in epilepsy remains unclear. This study aimed to investigate the effects and underlying mechanisms of S1P in a pentylenetetrazol (PTZ)-induced mouse model of epilepsy.</div></div><div><h3>Methods</h3><div>Male C57BL/6 mice were administered PTZ (33 mg/kg, i.p.) every other day for a total of 15 injections to establish a seizure-kindling model. S1P (0.5 mg/mL) was administered intraperitoneally during the subsequent treatment period. Seizure activity was assessed using electroencephalographic (EEG) recordings. Cognitive function was evaluated with the Morris water maze. Hippocampal neuronal morphology was examined via Nissl staining. The expression levels of IL-1β mRNA and precursor protein in the hippocampus were measured by qRT-PCR and Western blotting, respectively.</div></div><div><h3>Results</h3><div>S1P treatment significantly reduced seizure frequency and amplitude, shortened seizure duration, and ameliorated EEG abnormalities in epileptic mice. In behavioral assays, S1P improved spatial learning and memory performance. Histological analysis demonstrated reduced neuronal degeneration and preservation of hippocampal architecture in S1P-treated epileptic mice. Furthermore, S1P markedly decreased hippocampal IL-1β expression at both the mRNA and protein levels.</div></div><div><h3>Conclusions</h3><div>S1P exerts anti-seizure and neuroprotective effects in PTZ-induced epileptic mice and attenuates IL-1β–mediated neuroinflammation. These findings suggest that the S1P–IL-1β axis may represent a promising therapeutic target for epilepsy and its associated cognitive impairments.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"875 ","pages":"Article 138527"},"PeriodicalIF":2.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced antidepressant effects of fluoxetine combined with quercetin: studies in vitro and in vivo","authors":"Ran Yang ,&nbsp;Yifan Mao ,&nbsp;Jialin Yang ,&nbsp;Hai Ma ,&nbsp;Jianying Shen","doi":"10.1016/j.neulet.2026.138507","DOIUrl":"10.1016/j.neulet.2026.138507","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aims to explore the enhanced antidepressant effects of the commonly used depressant fluoxetine combined with a dietary supplement quercetin, using both <em>in vitro</em> and <em>in vivo</em> models.</div></div><div><h3>Methods</h3><div><em>In vitro</em>, we established both hydrogen peroxide (H₂O₂)-damaged and glutamate-damaged SH-SY5Y cells as cellular models. SH-SY5Y cells were exposed to 250 μM H₂O₂ or 16 mM glutamate and co-treated with 1 μM fluoxetine, 10 μM quercetin, or their combination for 24 h. Cell viability was detected.<!--> <em>In vivo</em>, we applied a chronic unpredictable mild stress (CUMS) animal model. C57BL/6 mice were treated with fluoxetine (5 or 10 mg/kg), quercetin (40 mg/kg), or their combinations. Depressive-like behaviors including Sucrose preference test (SPT), Tail suspension test (TST), and Forced swimming test (FST) were assessed. Nissl staining was carried out for observing changes in hippocampal neurons.</div></div><div><h3>Results</h3><div>Fluoxetine combined with quercetin protected SH-SY5Y cells from H₂O₂– or glutamate-induced damage, improved depressive-like behaviors and reduced hippocampal neuronal injury in CUMS mice, demonstrating enhanced antidepressant effects compared to monotherapy.</div></div><div><h3>Conclusion</h3><div>Combining fluoxetine with quercetin enhances antidepressant effects, suggesting a way to reduce the clinically required dosage of fluoxetine, thereby reducing its side effects.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"874 ","pages":"Article 138507"},"PeriodicalIF":2.0,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medial prefrontal Cortex, dopamine and glutamate modulation in regulating Reward-Seeking and frustration responses","authors":"Crysvane Araújo de Oliveira Lima ,&nbsp;Polliany da Silva Mendonça ,&nbsp;Joelson Germano Crispim ,&nbsp;Roger Luis da Silva ,&nbsp;Ryan Cordeiro Silva ,&nbsp;Lucas Felipe de Melo Alcantara ,&nbsp;Filipe Silveira Duarte ,&nbsp;Moacyr Jesus de Melo Rego ,&nbsp;Maira Galdino da Rocha Pitta ,&nbsp;Michelly Cristiny Pereira ,&nbsp;Michelle Melgarejo da Rosa","doi":"10.1016/j.neulet.2026.138506","DOIUrl":"10.1016/j.neulet.2026.138506","url":null,"abstract":"<div><h3>Background</h3><div>Behavior is often reinforced by rewarding experiences, which promote actions that yield positive outcomes contributing to adaptive decision-making. However, the absence of an anticipated reward can provoke negative emotional responses, such as frustration and anxiety, potentially leading to maladaptive behaviors. Understanding how the brain responds to reward and its omission is a growing focus in neuroscience, especially regarding how neurotransmitter systems in key circuits manage unmet expectations. The medial prefrontal cortex (mPFC), a central integrative hub, regulates downstream regions to process both rewarding and aversive outcomes. Although dopamine is known to guide reward prediction and adaptive behavior, the specific roles of dopaminergic and glutamatergic pathways in the mPFC remain unclear. <strong>Methods:</strong> In this study, we investigated the influence of mPFC and the differential roles of dopaminergic D2 and NMDA receptors within the mPFC on reward-seeking behaviors using a cued sucrose-seeking task. <strong>Results:</strong> Our results show that D2 dopamine receptor and NMDA receptor activity in the mPFC are essential for maintaining reward-seeking behaviors when expected rewards are omitted, highlighting dopamine and glutamate’s role in sustaining reward-persistent behavior. Conversely, only D2 blockade into mPFC affected cue-reward seeking behavior. Solely NMDA blockage in the mPFC and mPFC silencing reduced anxiety, suggesting a nuanced role for mPFC and glutamatergic signaling in managing the emotional response to unmet expectations. <strong>Conclusion:</strong> These findings provide new insights into how distinct neurotransmitter systems in the mPFC and mPFC itself contribute to the behavioral and emotional adjustments following reward and reward omission.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"874 ","pages":"Article 138506"},"PeriodicalIF":2.0,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutant glial fibrillary acidic protein reduces the capacity for glutamate uptake in hippocampal astrocytes","authors":"Yoshihiko Yamazaki ,&nbsp;Hiroki Fujiwara ,&nbsp;Jun-Ichi Goto ,&nbsp;Kenji F. Tanaka","doi":"10.1016/j.neulet.2026.138511","DOIUrl":"10.1016/j.neulet.2026.138511","url":null,"abstract":"<div><div>Astrocytes preserve synaptic function and maintain excitatory–inhibitory balance by regulating neurotransmitter homeostasis, notably through the clearance of glutamate from the extracellular space. This process is essential for preventing excitotoxicity in the central nervous system. Mutations in glial fibrillary acidic protein (GFAP) are associated with astrocytic dysfunction, leading to neurological symptoms, e.g., seizures. Although such mutations are implicated in neurological disorders including Alexander disease, their direct impact on the astrocytic uptake of synaptically released glutamate has not been demonstrated. Here, we assessed glutamate uptake in hippocampal astrocytes of mice expressing mutant GFAP using whole-cell recordings of transporter-mediated currents in acute hippocampal slices. Glutamate release into the synaptic cleft varied according to the intensity of afferent fiber stimulation, but transporter current amplitudes did not differ significantly between mutant and control mice under baseline conditions. In contrast, when adenosine A₁ receptors were blocked to relieve the tonic inhibition of glutamate release, transporter currents were significantly smaller in mutant mice than in controls at high stimulation intensities. These findings indicate that astrocytes expressing mutant GFAP exhibit impaired glutamate uptake capacity, which may be insufficient to prevent excitotoxicity or seizures under conditions of excessive glutamate release.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"874 ","pages":"Article 138511"},"PeriodicalIF":2.0,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}