Neurobiology of Disease最新文献

{"title":"Effects of trace element dysregulation on brain structure and function in spinocerebellar Ataxia type 3","authors":"LiHua Deng ,&nbsp;Liu Feng ,&nbsp;JingWen Li ,&nbsp;YongHua Huang ,&nbsp;PeiLing Ou ,&nbsp;LinFeng Shi ,&nbsp;Hui Chen ,&nbsp;YuHan Zhang ,&nbsp;LiMeng Dai ,&nbsp;Yuan He ,&nbsp;Chen Wei ,&nbsp;HuaFu Chen ,&nbsp;Jian Wang ,&nbsp;Leinian Li ,&nbsp;Chen Liu","doi":"10.1016/j.nbd.2025.106816","DOIUrl":"10.1016/j.nbd.2025.106816","url":null,"abstract":"<div><div>Spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disorder caused by excess CAG repeats in the <em>ATXN3</em> gene, leads to progressive cerebellar ataxia and other symptoms. The results of previous studies suggest that trace element dysregulation contributes to neurodegenerative disorder onset. Here, we investigated the relationships of trace element dysregulation with CAG repeat length, clinical severity, and brain structural and functional connectivity in 45 patients with SCA3 and 44 healthy controls (HCs). Blood levels of lithium (Li), selenium (Se), and copper (Cu) were significantly lower in patients with SCA3 than in HCs; Li and Se levels were negatively correlated with CAG repeat length, especially in the manifest subgroup. Diffusion tensor imaging combined with resting-state functional magnetic resonance imaging revealed that Li levels were negatively correlated with fractional anisotropy in the white matter (WM) of bilateral frontal and parietal regions; tractography mapping showed disorder structural connectivity of Li-associated region nerve fiber pathways in patients with SCA3. Dynamic causal modeling analyses showed bidirectional causal connectivity from the inferior parietal lobule(IPL) to the cerebellum was significantly correlated with the blood level of Li in patients with SCA3. Time series correlation-based functional connectivity analysis revealed that the intrinsic connectivities of the bilateral dorsal premotor cortex(PMd) and IPL with local cerebellar regions were significantly weaker in patients with SCA3 than in HCs. Our results suggest that trace element dysregulation, especially Li deficiency, induces brain alterations and clinical manifestations in patients with SCA3; Li supplementation may be beneficial for WM or astrocytes in this patient population.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106816"},"PeriodicalIF":5.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glymphatic dysfunction and neurodegeneration in ALS: Longitudinal insights from rNLS8 TDP-43 mice","authors":"Akram Zamani ,&nbsp;Adam K. Walker ,&nbsp;David K. Wright","doi":"10.1016/j.nbd.2025.106832","DOIUrl":"10.1016/j.nbd.2025.106832","url":null,"abstract":"<div><div>Dysfunctional Tar DNA binding protein-43 (TDP-43) is found in approximately 95 % of all people with amyotrophic lateral sclerosis (ALS). Recent evidence suggests that the glymphatic system, which clears the brain of waste proteins, is impaired in ALS and may contribute to the accumulation of TDP-43. This study extends this work to investigate how glymphatic function changes over time in the rNLS8 doxycycline (Dox)-dependent TDP-43 mouse model of ALS. Motor function, advanced MRI biomarkers of neurodegeneration, and cortical glymphatic pathway gene expression were assessed together with dynamic contrast-enhanced MRI (DCE-MRI) assessment of glymphatic function at 0-, 3-, 7-, and 21-days after removing mice from Dox feed to initiate cytoplasmic human TDP-43 expression. A trend toward increased glymphatic influx was observed at 3-days post-Dox, together with MRI evidence of brain changes that occurred in the absence of hind-limb clasping and motor impairment. Glymphatic flow is facilitated by aquaporin-4 (AQP4) water channels polarized to astrocytic end feet. We found that while glymphatic function normalized to control levels at 7-days post-Dox, AQP4 expression in the cortex was significantly decreased. After 3-weeks of human TDP-43 expression, glymphatic dysfunction, weight loss, neurodegeneration, motor impairments and astrogliosis were observed. Our findings highlight early glymphatic dysfunction in ALS, suggesting its potential as a therapeutic target.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106832"},"PeriodicalIF":5.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143236057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binding of HCN channels to GABAB receptors in dopamine neurons of the VTA limits synaptic inhibition and prevents the development of anxiety","authors":"Enrique Pérez-Garci ,&nbsp;Kateryna Pysanenko ,&nbsp;Giorgio Rizzi ,&nbsp;Florian Studer ,&nbsp;Daniel Ulrich ,&nbsp;Thorsten Fritzius ,&nbsp;Simon Früh ,&nbsp;Alessandra Porcu ,&nbsp;Valérie Besseyrias ,&nbsp;Adolf Melichar ,&nbsp;Martin Gassmann ,&nbsp;Tania Rinaldi Barkat ,&nbsp;Rostislav Tureček ,&nbsp;Kelly R. Tan ,&nbsp;Bernhard Bettler","doi":"10.1016/j.nbd.2025.106831","DOIUrl":"10.1016/j.nbd.2025.106831","url":null,"abstract":"<div><div>During GABAergic synaptic transmission, G protein-coupled GABA_B receptors (GBRs) activate K⁺ channels that prolong the duration of inhibitory postsynaptic potentials (IPSPs). We now show that KCTD16, an auxiliary GBR subunit, anchors hyperpolarization-activated cyclic nucleotide-gated (HCN) channels containing HCN2/HCN3 subunits to GBRs. In dopamine neurons of the VTA (DA^VTA neurons), this interaction facilitates activation of HCN channels via hyperpolarization during IPSPs, counteracting the GBR-mediated late phase of these IPSPs. Consequently, disruption of the GBR/HCN complex in <em>KCTD16</em>^−/− mice leads to prolonged optogenetic inhibition of DA^VTA neuron firing. <em>KCTD16</em>^{<em>−/−</em>} mice exhibit increased anxiety-like behavior in response to stress - a behavior replicated by CRISPR/Cas9-mediated <em>KCTD16</em> ablation in DA^VTA neurons or by intra-VTA infusion of an HCN antagonist in wild-type mice. Our findings support that the retention of HCN channels at GABAergic synapses by GBRs in DA^VTA neurons provides a negative feedback mechanism that restricts IPSP duration and mitigates the development of anxiety.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106831"},"PeriodicalIF":5.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abnormal neuronal activity in the subthalamic nucleus contributes to dysarthria in patients with Parkinson's disease.","authors":"Yu Diao, Zixiao Yin, Baotian Zhao, Yichen Xu, Yin Jiang, Yanling Yin, Anchao Yang, Yanming Zhu, Jan Hlavnicka, Jianguo Zhang","doi":"10.1016/j.nbd.2025.106830","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106830","url":null,"abstract":"<p><strong>Background: </strong>This study investigated the subthalamic nucleus (STN) function and deep brain stimulation (DBS) effects on single-unit activity (SUA) in Parkinson's disease (PD) patients with dysarthria.</p><p><strong>Methods: </strong>After presurgical speech analysis, we recorded STN neuronal activities while PD patients (n = 16) articulated Chinese Pinyin consonants. The Pinyin consonants were categorized by the manner and place of articulation for SUA cluster analysis. The cohort was then divided into normal articulation and dysarthria groups based on diadochokinetic (DDK) assessments. The STN SUA patterns, represented by the mean firing rate (FR), peak time, and response intensity during articulation, were analyzed and compared between the two groups. Finally, a stimulation cohort of 7 PD patients was included to test articulation and SUA pattern changes following intraoperative DBS.</p><p><strong>Results: </strong>Clustering analysis of STN neuronal firing patterns demonstrated that neurons encode articulation by grouping consonants with the same manner of articulation into distinct clusters. Using k-means clustering, we further classified SUAs into two waveform types: negative spikes (type 1) and positive spikes (type 2). Dysarthria patients exhibited an increased mean FR of type 1 spikes and a reduced response intensity of type 2 spikes. During intraoperative stimulation, PD patients showed accelerated DDK, accompanied by a decrease in type 1 mean FR and an increase in type 2 mean FR.</p><p><strong>Conclusion: </strong>Our findings indicate the crucial role of the STN in consonant encoding and dysarthria at the single-unit level. Both SUA firing patterns in the STN and DDK performance can be modulated by DBS.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106830"},"PeriodicalIF":5.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating cortical neurovascular involvement in Huntington's disease using human brain tissue microarrays","authors":"Adelie Y.S. Tan ,&nbsp;Lance C.M.G. Martinez ,&nbsp;Helen C. Murray ,&nbsp;Nasim F. Mehrabi ,&nbsp;Lynette J. Tippett ,&nbsp;Clinton P. Turner ,&nbsp;Maurice A. Curtis ,&nbsp;Richard L.M. Faull ,&nbsp;Mike Dragunow ,&nbsp;Malvindar K. Singh-Bains","doi":"10.1016/j.nbd.2025.106829","DOIUrl":"10.1016/j.nbd.2025.106829","url":null,"abstract":"<div><div>Although the genetic basis of Huntington's disease (HD) has been determined, the underlying pathophysiological mechanisms contributing to neurodegeneration remain largely unknown. In recent years, increasing evidence has posited vascular dysfunction as a significant early event in disease pathogenesis; however, these processes remain to be fully elucidated. High-content immunohistochemical screening studies were conducted on HD middle temporal gyrus (MTG) human brain tissue microarrays (TMAs) to investigate various components of the vascular system, including endothelial cells (UEA-1), pericytes (PDGFRβ), vascular smooth muscle cells (αSMA), extracellular matrix components (ECM; collagen IV and fibronectin), and leakage markers (haemoglobin and fibrinogen). Analyses of vascular markers revealed an increase in the number of vessels in the HD TMA cohort which was associated with advancing striatal pathology and earlier symptom onset. Furthermore, our findings highlight the preservation of pericytes, vascular smooth muscle cells, ECM components, and blood-brain barrier integrity in the HD MTG. Collectively, the TMA findings allude to mild vascular remodelling in the temporal cortex which is known to present with a lesser degree of neuronal degeneration in HD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106829"},"PeriodicalIF":5.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling a mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in Mucopolysaccharidosis VII","authors":"Nishan Mandal ,&nbsp;Apurba Das ,&nbsp;Rupak Datta","doi":"10.1016/j.nbd.2025.106825","DOIUrl":"10.1016/j.nbd.2025.106825","url":null,"abstract":"<div><div>Cognitive disability and neurodegeneration are prominent symptoms of Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. Yet, the mechanism of neurodegeneration in MPS VII remains unclear thereby limiting the scope of targeted therapy. We aimed to bridge this knowledge gap by employing the β-glucuronidase-deficient (CG2135^−/−) <em>Drosophila</em> model of MPS VII. Taking cues from our initial observation that the adult CG2135^−/− flies displayed enhanced susceptibility to starvation, we investigated potential impairments in the autophagy-lysosomal clearance machinery in their brain to dissect the underlying cause of neurodegeneration. We found that both autophagosome biogenesis and lysosome-mediated autophagosomal turnover were impaired in the CG2135^−/− fly brain. This was evidenced by lower Atg8a-II levels, reduced Atg1 and Ref(2)P expression along with accumulation of lipofuscin-like inclusions and multilamellar bodies. Mitophagy was also found to be defective in their brain, resulting in buildup of enlarged mitochondria with distorted cristae and reduced membrane potential. This, in turn, compromised mitochondrial function, as reflected by drastically reduced brain ATP levels. Energy depletion triggered apoptosis in neuronal as well as non-neuronal cells of the CG2135^−/− fly brain, where apoptotic dopaminergic neurons were also detected. Interestingly, resveratrol treatment corrected the mitophagy defect and prevented ATP depletion in the CG2135^−/− fly brain, providing an explanation for its neuroprotective effects. Collectively, our study reveals a pharmacologically targetable mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in MPS VII.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106825"},"PeriodicalIF":5.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143236058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole transcriptome analysis of unmutated sporadic ALS patients' peripheral blood reveals phenotype-specific gene expression signature","authors":"Francesca Dragoni ,&nbsp;Maria Garofalo ,&nbsp;Rosalinda Di Gerlando ,&nbsp;Bartolo Rizzo ,&nbsp;Matteo Bordoni ,&nbsp;Eveljn Scarian ,&nbsp;Camilla Viola ,&nbsp;Veronica Bettoni ,&nbsp;Giuseppe Fiamingo ,&nbsp;Danilo Tornabene ,&nbsp;Lucia Scanu ,&nbsp;Orietta Pansarasa ,&nbsp;Luca Diamanti ,&nbsp;Stella Gagliardi","doi":"10.1016/j.nbd.2025.106823","DOIUrl":"10.1016/j.nbd.2025.106823","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is an adult neurodegenerative disorder. According to clinical criteria, ALS patients can be classified into eight subgroups: classic, bulbar, pyramidal, pure lower motor neuron, flail arm, pure upper motor neuron, flail leg, and respiratory. There are no well-established molecular biomarkers for early diagnosis, prognosis, and progression monitoring of this fatal disease. Classification based on clinical phenotypes could be associated with peculiar gene expression patterns shaped during lifespan, allowing the identification of specific sporadic ALS (sALS) subtypes with less heterogeneous clinical and biological features. Our objective was to define a phenotype-specific transcriptomic signature of distinct ALS phenotypes, and lay the foundation for biomarkers development. We characterized 48 sALS patients by clinical and paraclinical parameters, and subdivided them in “Classic” (<em>n</em> = 12), “Bulbar” (<em>n</em> = 10), “Flail Arm” (<em>n</em> = 7), “Flail Leg” (n = 10) and “Pyramidal” (<em>n</em> = 9) phenotypes. RNAs extracted from patients' PBMCs and 19 controls were sequenced. Our analysis allowed the visualization of gene expression differential clusters between patients and controls. Interestingly, only one gene (Y3_RNA, a misc_RNA component of the Ro60 ribonucleoprotein involved in cellular response to interferon-alpha) was upregulated at different levels across all phenotypes, whereas other genes appeared phenotype-specific. The work proposed stress the innovative view of ALS as a multi-systemic disorder rather than a pure motor neuron-associated and ‘neurocentric’ pathology. The possibility to cluster ALS patients based on their molecular signature pave the way for future personalized clinical trials and early diagnosis.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106823"},"PeriodicalIF":5.1,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network-wide effects of pallidal deep brain stimulation normalised abnormal cerebellar cortical activity in the dystonic animal model","authors":"Fabiana Santana Kragelund ,&nbsp;Konstantinos Spiliotis ,&nbsp;Marco Heerdegen ,&nbsp;Tina Sellmann ,&nbsp;Henning Bathel ,&nbsp;Anika Lüttig ,&nbsp;Angelika Richter ,&nbsp;Jens Starke ,&nbsp;Rüdiger Köhling ,&nbsp;Denise Franz","doi":"10.1016/j.nbd.2024.106779","DOIUrl":"10.1016/j.nbd.2024.106779","url":null,"abstract":"<div><h3>Background</h3><div>Deep brain stimulation (DBS) targeting globus pallidus internus (GPi) is a recognised therapy for drug-refractory dystonia. However, the mechanisms underlying this effect are not fully understood. This study explores how pallidal DBS alters spatiotemporal pattern formation of neuronal dynamics within the cerebellar cortex in a dystonic animal model, the dt^sz hamster.</div></div><div><h3>Methods</h3><div>We conducted in vitro analysis using a high-density microelectrode array (HD-MEA) in the cerebellar cortex. For investigating the spatiotemporal pattern, mean firing rates (MFR), interspike intervals (ISI), spike amplitudes, and cerebellar connectivity among healthy control hamsters, dystonic dt^sz hamsters, DBS- and sham-DBS-treated dt^sz hamsters were analysed. A nonlinear data-driven method characterised the low-dimensional representation of the patterns in MEA data.</div></div><div><h3>Results</h3><div>Our HD-MEA recordings revealed reduced MFR and spike amplitudes in the dt^sz hamsters compared to healthy controls. Pallidal DBS induced network-wide effects, normalising MFR, spike amplitudes, and connectivity measures in hamsters, thereby countervailing these electrophysiological abnormalities. Additionally, network analysis showed neural activity patterns organised into communities, with higher connectivity in both healthy and DBS groups compared to dt^sz.</div></div><div><h3>Conclusions</h3><div>These findings suggest that pallidal DBS exerts some of its therapeutic effects on dystonia by normalising neuronal activity within the cerebellar cortex. Our findings of reduced MFR and spike amplitudes in the dt^sz hamsters could be a hint of a decrease in neuronal fibres and synaptic plasticity. Treatment with pallidal DBS led to cerebellar cortical activity similar to healthy controls, displaying the network-wide impact of local stimulation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106779"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR-based epigenetic editing of Gad1 improves synaptic inhibition and cognitive behavior in a Tauopathy mouse model","authors":"Lei Wan,&nbsp;Ping Zhong,&nbsp;Pei Li,&nbsp;Yong Ren,&nbsp;Wei Wang,&nbsp;Mingjun Yu,&nbsp;Henry Y. Feng,&nbsp;Zhen Yan","doi":"10.1016/j.nbd.2025.106826","DOIUrl":"10.1016/j.nbd.2025.106826","url":null,"abstract":"<div><div>GABAergic signaling in the brain plays a key role in regulating synaptic transmission, neuronal excitability, and cognitive processes. Large-scale sequencing has revealed the diminished expression of GABA-related genes in Alzheimer's disease (AD), however, it is largely unclear about the epigenetic mechanisms that dysregulate the transcription of these genes in AD. We confirmed that GABA synthesizing enzymes, <em>GAD1</em> and <em>GAD2</em>, were significantly downregulated in prefrontal cortex (PFC) of AD human postmortem tissues. A tauopathy mouse model also had the significantly reduced expression of GABA-related genes, as well as the diminished GABAergic synaptic transmission in PFC pyramidal neurons. To elevate endogenous Gad1 levels, we used the CRISPR/Cas9-based epigenome editing technology to recruit histone acetyltransferase p300 to <em>Gad1</em>. Cells transfected with a fusion protein consisting of the nuclease-null dCas9 protein and the catalytic core of p300 (dCas9^p300), as well as a guide RNA targeting <em>Gad1</em> promoter (gRNA^Gad1), had significantly increased <em>Gad1</em> mRNA expression and histone acetylation at <em>Gad1</em> promoter. Furthermore, the tauopathy mouse model with PFC injection of dCas9^p300 and gRNA^Gad1 lentiviruses had significantly elevated GABAergic synaptic currents and improved spatial memory. These results have provided an epigenetic editing-based gene-targeting strategy to restore synaptic inhibition and cognitive function in AD and related disorders.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106826"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury.","authors":"Vanessa O Torres, Jadwiga Turchan-Cholewo, Mary K Colson, Pavel Yanev, Daimen R S Britsch, Katherine Cotter, Annabel McAtee, Thomas Ujas, Domenico Mercurio, Xiangmei Kong, Erik J Plautz, Chaitanya R Joshi, Takeshi K Matsui, Eiichiro Mori, Ambar Cajigas-Hernandez, Kielen Zuurbier, Steve Estus, Mark P Goldberg, Nancy L Monson, Ann M Stowe","doi":"10.1016/j.nbd.2025.106819","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106819","url":null,"abstract":"<p><p>Following stroke, B cells enter brain regions outside of the ischemic injury to mediate functional recovery. Although B cells produce neurotrophins that support remote plasticity, including brain-derived neurotrophic factor (BDNF), it remains unclear which signal(s) activate B cells in the absence of infarct-localized pro-inflammatory cues. Activation of N-methyl-d-aspartate (NMDA)-type receptor (NMDAR) subunits on neurons can upregulate mature BDNF (mBDNF) production from a pro-BDNF precursor, but whether this occurs in B cells is unknown. We identified GluN2A and GluN2B NMDAR subunits on B cells that respond to glutamate and mediate nearly half of the glutamate-induced Ca²⁺ responses in activated B cell subsets. Ischemic stroke recruits GluN2A⁺ B cells into the ipsilesional hemisphere and both stroke and neurophysiologic levels of glutamate regulate gene and surface expression. Regardless of injury, pro-BDNF⁺ B localize to spleen/circulation whereas mBDNF⁺ B cells localize to the brain, including in aged male and female mice. We confirmed B cell-derived BDNF was required for in vitro and in vivo B cell-mediated neuroprotection. Lastly, GluN2A, GluN2B, glutamate-induced Ca²⁺ responses, and BDNF expression were all clinically confirmed in B cells from healthy donors, with BDNF⁺ B cells present in post-stroke human parenchyma. These data suggest that B cells express functional NMDARs that respond to glutamate, enhance NMDAR signaling with activation, and upregulate mature BDNF expression within the brain. This study identifies potential glutamate-induced neurotrophic roles for B cells in the brain; an immune response to neurotransmitters unique from established pro-inflammatory stimuli and relevant to any CNS-localized injury or disease.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106819"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}