Molecular Psychiatry最新文献

{"title":"Increasing conceptual clarity and confounders identification: a pragmatic way to enhance prognostic precision in ENIGMA clinical high risk for psychosis (CHR-P)","authors":"Andrea Raballo, Michele Poletti, Antonio Preti","doi":"10.1038/s41380-025-02948-8","DOIUrl":"https://doi.org/10.1038/s41380-025-02948-8","url":null,"abstract":"<p>Zhu and colleagues [1] utilized structural magnetic resonance imaging data from the ENIGMA Clinical High-Risk for Psychosis (CHR-P) Working Group cohort (based on 21 sites) to assess the ability of machine learning to predict psychosis. The primary outcome, transiton to psychosis, occurred in 144 out of 1165 CHR-P individuals (12.36%) and the study examined whether neuroimaging data processed through machine learning could discriminate between three CHR-P subgroups (transitioned, not transitioned, unknown outcome) and healthy controls.</p><p>The classifier achieved an accuracy of 85% on the training dataset and 73% on the independent confirmatory dataset. CHR-P individuals who did not transition to psychosis were more likely to be classified as healthy controls compared to those who developed psychosis (classification rate to healthy controls: CHR-P transitioned, 30%; CHR-P not transitioned, 73%; CHR-P unknown outcome, 80%).</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"55 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shank3 modulates Rpl3 expression and protein synthesis via mGlu5: implications for Phelan McDermid syndrome","authors":"Federica Giona, Stefania Beretta, Antonio Zippo, Alessia Stefanoni, Zaira Tomasoni, Cinzia Vicidomini, Luisa Ponzoni, Mariaelvina Sala, Carrie K. Jones, P. Jeffrey Conn, Tobias M. Boeckers, Carlo Sala, Chiara Verpelli","doi":"10.1038/s41380-025-02947-9","DOIUrl":"https://doi.org/10.1038/s41380-025-02947-9","url":null,"abstract":"<p>Mutations or deletions in the SHANK3 gene have been identified in up to 1% of autism spectrum disorder cases and are considered the primary cause of neuropsychiatric symptoms in Phelan McDermid syndrome (PMS). While synaptic dysfunctions have been extensively documented in the absence of Shank3, other mechanisms through which Shank3 may regulate neuronal functions remain unclear. In this study, we report that the ribosomal protein Rpl3 and overall protein synthesis are downregulated in the cortex and striatum of Shank3 knockout (KO) mice and in neurons differentiated from human-induced pluripotent stem cells (hiPSCs) derived from a PMS patient. Moreover, restoring Rpl3 expression in the striatum of Shank3 KO mice was sufficient to rescue protein synthesis and mitigate excessive grooming, suggesting that the behavioral alterations observed in Shank3 KO mice might be, at least in part, caused by Rpl3 downregulation and consequent impaired protein synthesis. Furthermore, we demonstrated that chronic inhibition of mGlu5 is sufficient to reduce Rpl3 expression, which in turn impairs global protein synthesis. Consequently, chronic treatment with VU0409551, a potent and selective mGlu5 positive allosteric modulator, rescues Rpl3 expression and the resulting reduction in protein synthesis, leading to long-lasting improvements in behavioral deficits in Shank3 KO mice Altogether, we propose a new role for Shank3 in modulating Rpl3 protein expression, ribosomal function, and protein synthesis by downregulating mGlu5 receptor activity.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"37 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S-ketamine exposure in early postnatal period induces social deficit mediated by excessive microglial synaptic pruning","authors":"Hongyu Zhong, Rou Xue, Yaning Han, Lei Liu, Jianshuai Zhao, Min Cai, Sa Wang, Pengfei Wei, Guangchao Zhao, Hailong Dong","doi":"10.1038/s41380-025-02949-7","DOIUrl":"https://doi.org/10.1038/s41380-025-02949-7","url":null,"abstract":"<p>The impact of general anesthetics on neurodevelopment is highly controversial in terms of clinical and preclinical studies. Evidence mounted in recent years indicated development of social cognitions was more susceptible to general anesthesia in early life. However, the behavioral characterization during adolescence and underlying mechanisms remains unclear. Herein, we observed that early postnatal <i>S</i>-ketamine exposure specifically induced deficits in sociability and social cognition via a machine learning assistant behavioral analysis toolbox- Social Behavioral Atlas (SBeA). Furthermore, <i>S</i>-ketamine exposure constantly activates microglia in the prefrontal cortex (PFC), mediating excessive synaptic pruning and dendritic structural abnormalities, leading to overexcitation of excitatory synaptic transmission. Notably, <i>S</i>-ketamine exposure activated Stat1-Arg1 pathway in microglia. Downregulating Arg1 expression or prophylactic administrating Arg1 selective inhibitor nor-NOHA could reverse microglial overactivation and attenuate the neurodevelopmental disturbance induced by <i>S</i>-ketamine exposure. Our study identifies the abnormal behavioral phenotypes in adolescence induced by early postnatal <i>S</i>-ketamine exposure and reveals a potential target for preventing anesthesia-related neurodevelopmental abnormalities.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"20 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroimaging changes in major depression with brief computer-assisted cognitive behavioral therapy compared to waitlist","authors":"Yvette I. Sheline, Michael E. Thase, Elizabeth A. Hembree, Nicholas L. Balderston, Frederick J. Nitchie, Alexandra S. Batzdorf, Walid Makhoul, Kevin G. Lynch","doi":"10.1038/s41380-025-02945-x","DOIUrl":"https://doi.org/10.1038/s41380-025-02945-x","url":null,"abstract":"<p>The goals of the current study were to determine the efficacy in major depressive disorder (MDD) of a shortened, computer-augmented cognitive behavioral therapy (CCBT) protocol and to determine brain plasticity effects following CCBT. Seventy-two MDD participants were randomized to CCBT or waitlist control groups and compared to 40 healthy controls (HCs). Functional MRI data were collected for all participants and repeated for patients following CCBT (five therapist-administered manualized CBT sessions plus computer training exercises). Linear mixed-effects models evaluated changes in depression scores throughout treatment and in connectivity from pre- to post-CCBT. Linear regression models compared connectivity differences between groups (MDD vs. HC). Following CCBT, there were decreases in MADRS and BDI (<i>p</i>s &lt; 0.001); there was more negative connectivity of dlPFC with sgACC and DMN with sgACC (<i>p</i>s &lt; 0.002); and there was more positive connectivity of FPN with nucleus accumbens, bilateral amygdalae, bilateral hippocampi, and sgACC and of DMN with ventral and dorsal bilateral anterior insulae (<i>p</i>s &lt; 0.01). There were no associations between change in MADRS and change in connectivity; however, there was an association between change in BDI and change in FPN–sgACC connectivity (<i>p</i> = 0.01). A shortened CBT schedule coupled with home computer exercises was associated with decreased depression symptoms and augmented PFC connectivity with multiple subcortical regions. One possible mechanism of the CCBT intervention is modulating PFC connectivity with subcortical regions, influencing top-down control of affective processes dysregulated in MDD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"56 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bidirectional emotional regulation through prefrontal innervation of the locus coeruleus","authors":"Mayumi Watanabe, Akira Uematsu, Joshua P. Johansen","doi":"10.1038/s41380-025-02944-y","DOIUrl":"https://doi.org/10.1038/s41380-025-02944-y","url":null,"abstract":"<p>Traumatic experiences produce powerful emotional memories which can subsequently be adaptively or pathologically modified through cognitive-evaluative mechanisms such as fear extinction learning. Noradrenaline from the brainstem locus coeruleus (LC) is activated during aversive emotion-inducing experiences, participates in extinction learning and is upregulated in individuals suffering from anxiety and trauma related disorders. The LC-noradrenaline system receives input from the medial prefrontal cortex (mPFC), a brain region important for cognitive and emotional control. However, it is unclear whether mPFC projections to LC regulate extinction and, if so, how distinct mPFC regions influence the LC to modulate emotional memories. Using viral based anatomical tracing techniques, we found that the LC receives topographically organized projections from the prelimbic (PL) and infralimbic (IL) subregions of mPFC in rats. Optogenetic inhibition approaches revealed that PL and IL inputs to LC inhibit or facilitate, respectively, the extinction of aversive memories. Moreover, LC-projecting neurons in PL and IL exhibit distinct activity patterns during extinction learning, with IL-to-LC neurons displaying sustained, sensory cue-evoked activation, while activity in PL-to-LC inputs is elevated during periods of externally and internally generated aversive emotional responding. Together, these results demonstrate that mPFC subregions opposingly regulate emotional memory extinction through their projections to the LC-noradrenaline system. These findings have important implications for understanding trauma related disorders which arise in part due to disrupted cognitive-emotional evaluations and impaired extinction.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"131 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammatory fluid biomarkers in patients with Alzheimer’s disease: a systematic literature review","authors":"Michael T. Heneka, Serge Gauthier, Sagar Anil Chandekar, Julie Hviid Hahn-Pedersen, Marie A. Bentsen, Henrik Zetterberg","doi":"10.1038/s41380-025-02939-9","DOIUrl":"https://doi.org/10.1038/s41380-025-02939-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Introduction</h3><p>Neuroinflammation is associated with both early and late stages of the pathophysiology of Alzheimer’s disease (AD). Fluid biomarkers are gaining significance in clinical practice for diagnosis in presymptomatic stages, monitoring, and disease prognosis. This systematic literature review (SLR) aimed to identify fluid biomarkers for neuroinflammation related to clinical stages across the AD continuum and examined long-term outcomes associated with changes in biomarkers.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The SLR was conducted per the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We used PubMed®, Embase®, and Cochrane Collaboration databases to search for articles in English (between 2012 and 2022) on AD or mild cognitive impairment due to AD, using “neuroinflammation” or other “immune” search strings. Two independent reviewers screened titles and examined data from full-text articles for the SLR.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>After the initial screening, 54 studies were prioritized for data extraction based upon their relevance to the SLR research questions. Nine studies for YKL-40, seven studies for sTREM2, and 11 studies for GFAP examined the relationship between the neuroinflammatory biomarkers and the clinical stage of the disease. Nine longitudinal studies further explored the association of fluid biomarkers with long-term clinical outcomes of disease. Cerebrospinal fluid (CSF) levels of YKL-40 were elevated in patients with AD dementia, while CSF sTREM2 levels were more strongly associated with preclinical and early symptomatic stages of AD. Plasma GFAP levels remained consistently elevated both in patients with AD dementia and individuals in preclinical stages with β-amyloid pathology. Longitudinal changes in plasma GFAP appeared to be predictive of cognitive decline in patients over time.</p><h3 data-test=\"abstract-sub-heading\">Discussion</h3><p>Neuroinflammatory biomarkers are associated with AD progression. More longitudinal studies in the preclinical and MCI stages of AD are needed to validate fluid biomarkers for diagnosis, disease monitoring, and prognosis in clinical practice.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"50 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paternal age, de novo mutation, and age at onset among co-affected schizophrenia sib-pairs: whole-genome sequencing in multiplex families","authors":"Yen-Chen A. Feng, Wei J. Chen, Mei-Chen Lin, Jacob Shujui Hsu, Chi-Fung Cheng, Chih-Min Liu, Hai-Gwo Hwu, Yen-Tsung Huang, Tzu-Pin Lu, Shi-Heng Wang","doi":"10.1038/s41380-025-02942-0","DOIUrl":"https://doi.org/10.1038/s41380-025-02942-0","url":null,"abstract":"<p>Whether delaying fatherhood leads to more mutations, thereby resulting in adverse psychiatric outcomes in offspring, remains under debate. No study has directly examined the role of de novo mutations (DNMs) between paternal age and offspring psychiatric outcomes. This study aimed to explore the association between paternal age, the number of DNMs, and age at onset of schizophrenia by sequencing the whole genome of multiplex schizophrenia families. Whole-genome sequencing (30x) was performed in 5 Taiwanese families, each comprising 3 co-affected siblings and healthy parents. Causal mediation analyses were used to explore the mediating role of DNMs in the paternal age effect. Paternal age predicted increased DNMs (+1.50 DNMs/year, 95% CI: 0.81, 2.19, p &lt; 0.0001) over maternal age (+0.09 DNMs/year, 95% CI: −1.01, 1.19, p = 0.87). The effect of paternal age on the number of DNMs varied across families. Each additional DNM resulted in a 0.16-year earlier onset age of schizophrenia (95% CI: 0.04, 0.27, p = 0.009). The estimated direct effect of paternal age on the onset of schizophrenia was −0.82 (95% CI: −0.90, −0.73), while the indirect effect through DNMs was −0.32 (95% CI: −0.47, −0.17). The proportion mediated via DNMs was 28.04% (95% CI: 18.19%, 37.89%). The mediation analyses showed that 30% of the observed association of paternal age with onset age of schizophrenia might be mediated through paternal age-related DNMs. Our study, the first to directly quantify the mediating effect of DNMs, provides support for a causal role of paternal age-related mutations in the increased psychiatric risk in offspring.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"18 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morphological alterations of the thymus gland in individuals with schizophrenia","authors":"Qiannan Zhao, Xia Wei, Wei Yu, Xing Li, Ziyang Gao, Senhao Liu, Zhiqin Liu, Kunxuan Wang, Jeffrey R. Bishop, Hongbo Hu, Chunyan Luo, Yuan Xiao, Na Hu, Bo Tao, Fei Zhu, Qiyong Gong, Su Lui","doi":"10.1038/s41380-025-02946-w","DOIUrl":"https://doi.org/10.1038/s41380-025-02946-w","url":null,"abstract":"<p>Despite its critical function in the immune system and accumulating evidence of immunological abnormalities in schizophrenia, the thymus has long been overlooked. We aimed to investigate thymic morphological alterations and their corresponding heterogeneity in patients with schizophrenia. Imaging-derived thymic morphology was assessed and compared between 419 patients with schizophrenia and 460 age- and sex-matched control participants aged 16–40 years who underwent chest computed tomography (CT) scanning. These included measurements reflecting thymic size and density, such as average maximal thickness, anteroposterior distance, and average CT attenuation, which were also used to identify patient subtypes based on an unsupervised machine learning algorithm. Once the thymus-based patient subtypes were identified, between-subtype differences in the thymic and blood immunometabolic profiles were further tested. Case-control comparisons revealed that patients had greater average maximal thickness (Glass’s delta [Δ] effect size = 0.37) but lower average CT attenuation (Δ = −0.18) in the thymus than controls. Two thymus-based subtypes with disparate thymic and blood immunometabolic profiles were identified. Specifically, Subtype 1 (containing 40.1% of patients) was characterized as greater average maximal thickness (Δ = 1.36) and longer anteroposterior distance (Δ = 0.71) but lower CT attenuation (Δ = −0.97), contrary to the abnormal patterns of Subtype 2. Furthermore, Subtype 1 had higher levels of blood immunometabolic profiles, such as lymphocyte count and lipid measures, than Subtype 2. Altered thymic morphology with considerable heterogeneity was first reported in schizophrenia, providing evidence for the immune hypothesis and facilitating the discovery of imaging biomarkers reflecting the immunometabolic status.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"18 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simple platelet biomarker is associated with symptom severity in major depressive disorder","authors":"Aksu Gunay, Steven D. Targum, Alex D. Leow, Olusola Ajilore, Mark M. Rasenick","doi":"10.1038/s41380-025-02941-1","DOIUrl":"https://doi.org/10.1038/s41380-025-02941-1","url":null,"abstract":"<p>Previous studies have shown that the heterotrimeric G protein, Gsalpha (Gsα), is ensconced predominantly in lipid rafts in acutely depressed subjects with major depressive disorder (MDD) in contrast to healthy controls, and that effective antidepressant treatment (ADT) facilitates translocation of Gsα from lipid rafts. The measurement of Gsα via prostaglandin E1 stimulation of adenylyl cyclase (PGE1 stimulation) has been proposed as a peripheral biomarker for assessing clinical status in MDD. We examined the Gsα biomarker in a new study. PGE1 stimulation was used to assess the coupling of Gsα with platelet adenylyl cyclase in depressed subjects in active treatment and healthy controls. The Quick Inventory of Depressive Symptomatology (QIDS-C₁₆) measured thresholds of symptom severity at two study visits spaced 2 weeks apart. QIDS-C₁₆ scores and PGE1 stimulated responses were stable between the two study visits. The QIDS-C₁₆ was inversely correlated with PGE1 stimulated responses at each visit (r_s = −0.33, r_s = −0.60, respectively). MDD subjects with mild-moderate depressive symptoms (defined by QIDS-C₁₆ ≥ 6) had significantly lower PGE1 stimulated responses than asymptomatic MDD subjects (QIDS-C₁₆ &lt; 6) or healthy controls (<i>p</i> = 0.001 and 0.002 respectively). MDD subjects with moderate depressive symptoms (QIDS-C₁₆ ≥ 10) had the lowest PGE1 responses of all subjects (Fisher’s exact = 0.012). These results support our earlier findings that a simple, high-throughput-capable platelet assay may be a useful biomarker to assess the clinical status of depressed subjects. Larger studies are needed to evaluate the utility of this biomarker for diagnosis and treatment response.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"9 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paranodal instability driven by axonal mitochondrial accumulation in ischemic demyelination and cognitive decline","authors":"Yiwei Feng, Min Guo, Tongyao You, Minjie Zhang, Jincheng Li, Junchao Xie, Sida Han, Hongchen Zhao, Yanfeng Jiang, Yanxin Zhao, Jintai Yu, Qiang Dong, Mei Cui","doi":"10.1038/s41380-025-02936-y","DOIUrl":"https://doi.org/10.1038/s41380-025-02936-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Subcortical ischemic demyelination is the primary cause of vascular cognitive impairment in the elderly. However, its underlying mechanisms remain elusive.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Using a bilateral common carotid artery stenosis (BACS) mouse model and an in vitro cerebellar slice model treated with low glucose-low oxygen (LGLO), we investigated a novel mechanism of vascular demyelination.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>This work identified syntaphilin-mediated docking of mitochondria as the initial event preceding ischemic demyelination. This axonal insult drives paranodal retraction, myelin instability, and subsequent cognitive impairment through excessive oxidation of protein 4.1B by mitochondrial ROS. Syntaphilin knockdown reestablished the balance of mitochondrial axoplasmic transport, reduced axonal ROS burden, and consequently decreased the abnormal oxidation of protein 4.1B, an essential component that secures the Caspr1/contactin-1/NF155 complex tethered to the axonal cytoskeleton βII-Spectrin within paranodes. This ultimately protected the paranodal structure and myelin and improved cognitive function.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Our findings reveal a distinct pathological characteristic of ischemic demyelination and highlight the therapeutic potential of modulating axonal mitochondrial mobility to stabilize myelin structures and improve vascular cognitive impairment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"11 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}