Molecular Psychiatry最新文献

{"title":"Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.","authors":"Samantha Corrà, Valeria Balmaceda, Carlo Viscomi","doi":"10.1038/s41380-026-03570-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03570-y","url":null,"abstract":"<p><p>Mitochondrial diseases, caused by mutations in either mitochondrial or nuclear DNA, are highly complex genetic disorders characterized by faulty oxidative phosphorylation. Adeno-associated virus (AAV)-based gene therapy with its broad and customizable tissue tropism achieved through natural and engineered serotypes offers a highly effective platform for delivering therapeutic genes to affected tissues. However, the intricate genetics and biology of mitochondria present unique challenges for the development of AAV-based therapies. While gene replacement therapy remains a viable strategy for correcting nuclear gene defects, mutations in mtDNA require specialized approaches, such as mitochondrially targeted, RNA-free base editors and nucleases capable of precise editing within the mitochondrial genome. As an alternative, allotopic expression, which involves expressing mitochondrial genes from the nuclear genome, is currently being evaluated in clinical trials but remains controversial, due to issues related to mitochondrial import and functional integration in the respiratory complexes. The clinical translation of AAV-mediated therapies for mitochondrial diseases still confronts several interrelated challenges, including efficient targeting of multiple affected organs, scalable and cost-effective vector manufacturing, and minimizing vector-associated toxicity. By integrating advanced genome editing technologies with sophisticated vector engineering and delivery strategies, AAV-based gene therapy stands as a transformative approach for addressing the broad and heterogeneous spectrum of primary mitochondrial disorders. Continued progress in overcoming current biological and technical barriers will be essential to realize the full therapeutic potential of AAVs.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777020","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":"Cognitive impairment preceding the onset of the first psychosis episode in schizophrenia.","authors":"Abraham Reichenberg, René S Kahn","doi":"10.1038/s41380-026-03625-0","DOIUrl":"https://doi.org/10.1038/s41380-026-03625-0","url":null,"abstract":"<p><p>Adults with schizophrenia exhibit substantial and widespread cognitive impairment, with subtle cognitive deficits already apparent in childhood and adolescence - many years prior to the onset of psychosis. Here, we focus on evidence from population-based research highlighting findings specific to cognitive impairment (as indexed by IQ) that precedes the onset of schizophrenia. We illustrate that (i) cognitive impairment worsens from early childhood onwards through to the onset of psychosis; (ii) this early and progressive cognitive impairment is rarely present in other psychotic disorders. At the same time, (iii) early cognitive impairment is not universal in schizophrenia; and (iv) a substantial role for genes affecting both schizophrenia and early life cognitive impairment has not been unequivocally proven. We suggest that a subgroup of patients with schizophrenia is characterized by progressive premorbid cognitive impairment. This group is developmentally distinguishable from the rest of patients with psychoses. Future studies should focus on understanding the (possibly unique) etiology in this neurodevelopmental subgroup of schizophrenia patients.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776977","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":"Exosomes in depression: mechanistic insights, diagnostic potential, and therapeutic opportunities.","authors":"Fei Wang, Jian Yang, Gang Wang","doi":"10.1038/s41380-026-03622-3","DOIUrl":"https://doi.org/10.1038/s41380-026-03622-3","url":null,"abstract":"<p><p>Exosomes are increasingly recognized as critical mediators of intercellular communication within the central nervous system and along the brain-periphery axis, with emerging relevance to the pathophysiology of depression. These nanoscale extracellular vesicles transport bioactive cargo-including microRNAs (miRNAs), proteins, lipids, and metabolites-that can modulate neuroinflammatory signaling, synaptic remodeling, hypothalamic-pituitary-adrenal (HPA) axis dynamics, and gut-brain communication. Converging evidence from human and preclinical studies suggests that alterations in circulating and brain-derived exosomal cargo are associated with major depressive disorder (MDD) and secondary depression following neurological insults such as traumatic brain injury (TBI), implicating shared inflammatory and synaptic pathways alongside distinct etiological drivers. Circulating neuron-enriched exosomes carrying miRNAs such as miR-16 and miR-124 have been proposed as minimally invasive biomarkers reflecting brain-relevant molecular alterations. However, most human data remain cross-sectional and associative, with limited longitudinal replication and incomplete validation of cellular origin. Therapeutically, mesenchymal stem cell (MSC)-derived exosomes demonstrate antidepressant-like effects in rodent models through modulation of microglial activation, enhancement of synaptic plasticity, and attenuation of neuroinflammatory cascades. Engineered exosomes further offer a potential platform for targeted delivery of anti-inflammatory or neuroplasticity-enhancing cargo. Induced pluripotent stem cell (iPSC)-derived exosomes represent a potentially scalable and standardizable therapeutic platform. Despite this promise, substantial barriers impede clinical translation. Isolation workflows-including ultracentrifugation, size-exclusion chromatography, and immunoaffinity capture-vary in yield, purity, and reproducibility, complicating cross-cohort comparability. Moreover, definitive attribution of vesicle origin in peripheral biofluids remains technically constrained, and standardized reporting frameworks are inconsistently applied. Advances in multi-omics profiling, high-throughput sequencing, mass spectrometry, and spatially resolved molecular analyses may improve mechanistic resolution and biomarker robustness. Collectively, exosome research in depression resides at an early but rapidly evolving translational stage. Rigorous methodological standardization, longitudinal cohort validation, and mechanistic dissection across primary and injury-related depression will be essential to determine whether exosome-based diagnostics and therapeutics can fulfill their potential within precision psychiatry.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776990","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":"Astrocytic connexin 43 hemichannel dysregulation drives prefrontal circuit dysfunction and schizophrenia-like behaviors","authors":"Liangliang Wang, Kai Xu, Yanhui Liao, Yujian Luo, Yehong Fang, Xinyue Zhang, Jun Wang, Kun Li, Dan Zhou, Shuangshuang Liu, Wei Chen, Lang Wang, Jinsong Tang","doi":"10.1038/s41380-026-03621-4","DOIUrl":"https://doi.org/10.1038/s41380-026-03621-4","url":null,"abstract":"Schizophrenia (SCZ) is hypothesized to arise from neural circuit dysfunction, but the role of non-neuronal cells remains poorly defined. While astrocytic connexin 43 (Cx43) facilitates both gap junction (GJ) coupling and hemichannel (HC)-mediated gliotransmitter release, its specific role in SCZ remains unclear. Here, we report elevated Cx43 expression in the prefrontal cortex of individuals with SCZ and investigate its functional relevance in an MK801-induced mouse model. In this model, medial prefrontal cortex (mPFC) Cx43 upregulation was associated with enhanced HC activity without affecting GJ coupling. Pharmacological blockade of Cx43 HC with TAT-Gap19 rescued SCZ-like behavioral and synaptic alterations, whereas astrocyte-specific Cx43 overexpression (Cx43 OE) in the mPFC of naive mice recapitulated behavioral abnormalities. Mechanistically, increased HC activity was linked to excessive astrocytic glutamate release, which was directly visualized using ex vivo two-photon imaging with an astrocyte-specific glutamate sensor and normalized by TAT-Gap19. Together, our results integrate human expression data with experimental evidence to implicate astrocytic Cx43 HC dysregulation in prefrontal circuit dysfunction relevant to SCZ and suggest that glial HC signaling warrants further investigation in SCZ pathophysiology.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"21 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751797","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":"Gut microbiome alterations are sex-dependently associated with brain abnormalities in a mouse model of Neurofibromatosis type I","authors":"Sonali N. Reisinger, Geraldine Kong, Nicholas van de Garde, Asim Muhammad, Pranav Adithya, Da Lu, Pamudika Kiridena, Carolina Gubert, Gabriel Dabscheck, Jonathan M. Payne, Anthony J. Hannan","doi":"10.1038/s41380-026-03609-0","DOIUrl":"https://doi.org/10.1038/s41380-026-03609-0","url":null,"abstract":"Neurofibromatosis type 1 (NF1) is a genetic condition presenting with variable symptomatology, however most individuals will demonstrate cognitive and behavioural difficulties, including autism. Using a heterozygous germline knockout mouse model of NF1 (Nf1 +/-), we performed in-depth behavioural evaluations encompassing learning and memory, stereotypy, social interaction, anxiety- and depression-like behaviour. Anatomical and functional studies of the brain and gastrointestinal tract were followed by the first investigation of gut microbiota composition (via full-length 16S rRNA sequencing) in a Nf1 +/- mouse model. The cognitive and autism-like behavioural phenotype seen in Nf1 +/- mice was accompanied by a striking increase in relative brain size which is highly relevant to clinical NF1. Furthermore, brain size was correlated with behaviour, supporting a potential mechanistic link. Nf1 +/- mice showed significant alterations in gut microbiota composition vs. Nf1 +/+ wild-type controls, with males additionally showing significant changes to species abundance of the Clostridium and Blautia genera, and the Lachnospiraceae family, findings which partially overlap with those in preclinical and clinical autism. Composition of associated functional pathways was not globally altered, however +/- mice showed significant changes in a pyrimidine deoxynucleotide biosynthesis pathway. In male Nf1 +/- mice, we also identified a genotype-specific host-microbial signature, pointing towards a mechanistic link between gut microbiome composition and brain size. These findings significantly expand our understanding of brain and behavioural abnormalities in this preclinical model of NF1 and, importantly, have uncovered the gut microbiome as a highly promising new area of research and a potential therapeutic target for these symptom clusters.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"26 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751799","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":"Alzheimer’s disease-like brain pattern biomarker: capturing risks and predicting disease onset","authors":"Peter Kochunov, Si Gao, Lauren E. Salminen, Neda Jahanshad, Talia M. Nir, Paul M. Thompson, Xiaoming Du, Bhim M. Adhikari, Alice Kochunov, Ryan Cassidy, Yizhou Ma, Joshua Chiappelli, Seth Ament, Yezhi Pan, Shuo Chen, Alan R. Shuldiner, Braxton D. Mitchell, L. Jair Soares, L. Elliot Hong","doi":"10.1038/s41380-026-03617-0","DOIUrl":"https://doi.org/10.1038/s41380-026-03617-0","url":null,"abstract":"Preventing Alzheimer’s disease (AD) requires early-warning biomarkers. We developed a Regional Vulnerability Index (RVI) that quantifies individual brain similarity to AD patients’ expected brain deficit patterns. We calculated regional effect sizes to establish brain deficit patterns in amyloid-positive AD cases compared to amyloid-negative healthy controls. RVI-AD was calculated as a linear index of individual similarity to this established brain pattern in AD. We demonstrated RVI-AD elevation associated with risk factors in 335 participants (mean age: 49 ± 13 years) in the Amish Connectome Project, followed by an independent sample consisting of 26,010 participants (mean age: 64 ± 7 years) from the UK Biobank. Genetic and cardiovascular risks were evaluated using APOE-e4 genotype and Framingham Cardiovascular Risk Scores (FCVRS), respectively. Additionally, we assessed the risk of converting from MCI to dementia in N = 1932 participants (mean age: ~74) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Healthy participants with the APOE-e4 allele had significantly elevated RVI-AD indices (p = 0.03 and 2·10−5, for ACP and UKBB samples respectively). FCVRS significantly contributed to higher RVI-AD in an interaction with APOE-e4-specific manner (p = 2·10−4 and 7·10−6 for ACP and UKBB samples respectively). In ADNI cohort, RVI-AD significantly predicted conversion from MCI to dementia in the next decade, particularly in the first three years (AUC = 70–74%, OR = 2.16, 95% CI = 1.8–2.6, p < 10−16). In healthy individuals, the RVI-AD detected the insidious impact of APOE-ε4 and cardiovascular risks in otherwise normally aging cohorts. Elevated RVI-AD also predicted conversion to dementia within ten years in the older, high-risk cohort. Further development of this brain-pattern similarity-based approach may yield a noninvasive, clinically accessible biomarker to aid early detection of the subtle to more imminent effects of AD risks.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751805","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":"Multiomics analysis identifies VPA-induced changes in neural progenitor cells, ventricular-like regions, and cellular microenvironment in dorsal forebrain organoids","authors":"Zeynep Yentür, Lizia Branco, Kseniia Sarieva, Daria Andreeva, Theresa Kagermeier, Christina Kulka, Mohamed A. Jarboui, Federico Colombo, Florencia Diaz, Pierre Collignon, Katharina Becker, Christine Selhuber-Unkel, Simone Mayer","doi":"10.1038/s41380-026-03585-5","DOIUrl":"https://doi.org/10.1038/s41380-026-03585-5","url":null,"abstract":"Pharmaceutical agents, such as antiepileptic medications, can cross fetal barriers and affect the developing brain. Prenatal exposure to the antiepileptic drug valproate (VPA) is associated with an increased risk of neurodevelopmental disorders, including congenital malformations and autism spectrum disorder. In animal models and neural organoids, VPA has been shown to alter signaling pathways, such as Wnt pathway, providing insights into VPA-induced neurodevelopmental defects. Here, we exposed dorsal forebrain organoids to VPA for 30 days and examined effects at the tissue, cellular, and molecular level. VPA treatment disrupted ventricular-like regions, indicating defects in cell-cell and cell-matrix interactions. Transcriptomics analysis confirmed altered expression of extracellular matrix (ECM) genes and single cell RNA sequencing analysis identified genes involved in microenvironment sensing, such as cellular mechanosensing and Hippo-YAP/TAZ signaling pathway. Finally, proteomics analysis corroborated that VPA alters the microenvironment of the human dorsal forebrain organoids by disrupting the secretion of ECM proteins. Altogether, our study suggests that VPA-treated dorsal forebrain organoids serve as a model to investigate the role of extracellular processes in brain development and to understand how their disruptions might contribute to neurodevelopmental disorders.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"250 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751801","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":"Blood-derived microRNA signatures associated with hippocampal structure and atrophy rate: findings from the Rhineland Study","authors":"Konstantinos Melas, Valentina Talevi, Mohammed Aslam Imtiaz, Dennis M. Krüger, Tonatiuh Pena-Centeno, André Fischer, N. Ahmad Aziz, Monique M. B. Breteler","doi":"10.1038/s41380-026-03611-6","DOIUrl":"https://doi.org/10.1038/s41380-026-03611-6","url":null,"abstract":"MicroRNAs (miRNAs) have been linked to brain disorders, but their relations with hippocampal structure and atrophy remain unexplored. As the hippocampus is pivotal for cognition and dementia, understanding these relations and their specificity for the hippocampus would elucidate miRNA involvement in brain health and neurodegeneration. Here, using population-based data, we cross-sectionally and longitudinally examined the associations of blood-derived miRNAs with left and right hippocampal volume, hippocampal asymmetry, and total brain volume. Expression of miRNAs and their putative target genes was measured at study baseline in whole blood using RNA sequencing. Brain imaging measures were examined at baseline and re-examined 4.60–8.02 years later using 3 T MRI. We investigated miRNA associations with imaging measures cross-sectionally using linear regression and longitudinally using linear mixed-effect models. Cross-sectionally, six miRNAs (miR-199a-3p, miR-199b-3p, miR-155-5p, miR-146a-5p, miR-6859-5p, miR-505-5p) were associated exclusively with left hippocampal volume. Longitudinally, another five miRNAs (miR-361-3p, miR-4473, miR-381-3p, miR-543, miR-370-3p) were associated with left hippocampal, right hippocampal, and total brain atrophy rates. Twenty-one miRNAs were exclusively associated with total brain atrophy rate. In whole blood, miRNAs identified in the cross-sectional analysis targeted genes related to brain development, memory, and synapse assembly. MiRNAs from the longitudinal analysis targeted genes related to axonal and dendritic growth. Several identified miRNAs were previously linked to neurodegeneration. Especially miR-146a-5p and miR-370-3p have been consistently linked to dementia and could be investigated as presymptomatic blood-based biomarkers. The brain-specific functions and interactions with target genes of identified miRNAs could be further investigated to develop therapeutic strategies against neurodegeneration.\u0000\u0000The alternative text for this image may have been generated using AI.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"11 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751803","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":"Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity.","authors":"Tae-Wook Woo, Yu-Jin Choi, Jun-Yeol Kim, Jin-Seok Lee, Chang-Gue Son","doi":"10.1038/s41380-026-03608-1","DOIUrl":"https://doi.org/10.1038/s41380-026-03608-1","url":null,"abstract":"<p><p>Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a major clinical challenge as a complex multisystemic disorder with no well-established pathophysiological mechanism, characterized by persistent fatigue and post-exertional malaise, along with unrefreshing sleep, cognitive impairment, and impaired stress recovery. Despite decades of investigation into the hypothalamic-pituitary-adrenal (HPA) axis, a definitive neuroendocrine hallmark has remained elusive due to inconsistent findings across various cortisol matrices. Therefore, this systematic review and meta-analysis aimed to provide an integrated understanding of HPA-axis regulation in ME/CFS. We identified 46 case-control studies (comprising 46 independent datasets, including 12 pharmacological challenge studies), involving 1388 ME/CFS patients (71.9% female; mean age 37.3 ± 6.2 years) and 1349 matched healthy controls. Meta-analyses showed lower salivary cortisol at awakening and in the morning. Reductions were also observed in 24-h urinary cortisol and hair cortisol. In pharmacological challenge tests, patients exhibited impaired cortisol release in response to adrenocorticotropic hormone (ACTH) stimulation and exaggerated suppression following glucocorticoid administration. Collectively, these alterations indicate reduced free cortisol availability and enhanced HPA-axis negative feedback sensitivity, consistent with a hyporeactive endocrine state in ME/CFS. This neuroendocrine hypo-reactivity may underlie hallmark clinical features such as unrefreshing sleep, post-exertional malaise, and severe fatigue, as well as cognitive slowing, emotional blunting, and diminished stress resilience frequently observed in ME/CFS and related functional disorders. Integrating neuroendocrine and psychological perspectives may help clarify mechanisms of chronic stress maladaptation and inform psychobiological interventions for fatigue syndromes.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776958","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":"IL-15 receptor alpha deficiency triggers depressive-like behaviors via enhanced microglial synapse pruning","authors":"Yue Tang, Yu Huang, Jing Pan, Chaolan Li, Jie Yang, Xunmin Tan, Kangan Hu, Lu Wen, Peijun Xie, Yuxiang Liu, Haotian Xu, Shixin Cao, Jianping Zhang, Yifan Li, Ping Liu, Minghao Yuan, Xiaodong Song, Jing Wu, Yi He, Ma-Li Wong, Julio Licinio, Peng Zheng","doi":"10.1038/s41380-026-03593-5","DOIUrl":"https://doi.org/10.1038/s41380-026-03593-5","url":null,"abstract":"Major Depressive Disorder (MDD) is a serious mental illness, and neuroinflammation is increasingly recognized as a contributor to its pathogenesis; however, the underlying cellular and molecular mechanisms remain largely unknown. In this study, we performed single-nucleus RNA sequencing to profile prefrontal cortex transcriptomics in interleukin-15 receptor subunit alpha knockout (Il15ra-/-) mice displaying depressive-like behaviors. Il15ra-/- mice exhibited cell-type-specific transcriptomic alterations, particularly affecting synapse assembly. Co-expression network analysis identified two gene clusters predominantly linked to synaptic pathways in microglia, excitatory neurons, and interneurons, suggesting dysregulated neuron-microglial interactions in depression. Morphological analysis revealed microglial activation and synapse remodeling driven by enhanced neuron-microglia communication via the CX3CL1/CX3CR1 signaling pathway. Pharmacological inhibition of CX3CL1/CX3CR1 signaling using a CX3CR1 antagonist reversed depressive-like behaviors and microglia-mediated excessive synapse pruning caused by IL-15RA deficiency. Collectively, these findings demonstrate that IL-15RA deficiency contributes to depression onset by modulating microglia-mediated synaptic remodeling, highlighting a targetable neuroimmune pathway for therapeutic interventions in MDD.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"53 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147734027","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}