Molecular Psychiatry最新文献

{"title":"Elevated NEGR1 in brain induces anxiety or depression-like phenotypes and synaptic dysfunction","authors":"Ya-Qi Zhang, Qing Zhang, Yi Yang, Li-Li Yu, Ning-Lin Fan, Yong Wu, Jun-Yang Wang, Xing-Lun Dang, Ying-Qi Guo, Cong Li, Guo-Lan Ma, Lu Wang, Yong-Bo Guo, Shi-Wu Li","doi":"10.1038/s41380-025-03052-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03052-7","url":null,"abstract":"<p>Single nucleotide polymorphisms (SNPs) within 1p31.1 region have shown significant associations with depression, and our prior functional genomics pinpointed a regulatory variant rs3101339 among them. However, its precise role in depression pathogenesis remains elusive. In this study, we employed a series of analytical and functional approaches, including regulatory element annotation, brain expression quantitative trait loci (eQTL), reporter gene assay, electrophoretic mobility shift assay (EMSA), and precise genome editing. Our results confirmed that rs3101339 is a causal variant within 1p31.1 with its risk allele C upregulating <i>NEGR1</i> expression. To further investigate the consequences of <i>NEGR1</i> upregulation, we overexpressed <i>NEGR1</i> in specific region of the mouse brain (including medial prefrontal cortex (mPFC) and ventral hippocampus (vHIP)) using stereotaxic injection. Behavioral assessments revealed that elevated <i>NEGR1</i> levels in the brain, particularly in the vHIP, resulted in working memory impairment as well as anxiety- and depression-like behaviors in mice. Neuronal sparse labeling assay and transmission electron microscopy revealed that <i>NEGR1</i> overexpressing in the vHIP leads to dendritic spine loss and synaptic ultrastructure abnormality. Immunoprecipitation-mass spectrometry (IP-MS) further identified 67 high-confidence proteins that interacted with NEGR1, many of which are involved in neurotransmitter exocytosis and synaptic vesicle endocytosis. Transcriptomic profiling revealed 94 differentially expressed genes in NEGR1-OE (vHIP) mice compared to control mice (<i>P</i> adj &lt; 0.05), which were enriched in myelination-related signaling pathways (such as myelination, ensheathment of neurons, axon ensheathment in central nervous system, etc.). Together, our findings implicated that the overexpression of the <i>NEGR1</i> gene in the mouse brain as a potential driver of anxiety- or depression-like phenotypes potentially through impairing synaptic function and myelination.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"21 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066790","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":"The evidence of influenza A virus infection during pregnancy as a risk factor for neuropsychiatric disorder in offspring","authors":"Jean-Paul Selten, Vera A. Morgan","doi":"10.1038/s41380-025-03059-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03059-0","url":null,"abstract":"<p><b>To the Editor</b>,</p><p>With interest we read the paper about the effects of infection with Influenza A virus on pregnant mice: disruption of maternal intestinal immunity and of foetal cortical development in a time- and dose-dependent manner [1]. However, we were surprised to read in the introduction of the paper that “epidemiological studies demonstrate that influenza A virus infection during pregnancy increases the prevalence of offspring neurodevelopmental disorders like schizophrenia, bipolar disorder and autism spectrum disorder (as reviewed in [2])”. The authors cite three papers that support an association with schizophrenia, one paper that does the same for bipolar disorder and one for autism spectrum disorder. Importantly, they do not mention dozens of studies that obtained negative results. The review cited by the authors [2] describes possible mechanisms that can lead to neuropsychiatric illness and is not a critical or systematic review of the existing epidemiological literature. The authors fail to mention two meta-analyses of studies on the relationship between maternal influenza during pregnancy and risk of schizophrenia or bipolar disorder in the child [3, 4], and a systematic review of studies on a wider range of neuropsychiatric outcomes, including autism spectrum disorder and intellectual disability [5]. Let us very briefly summarize the findings.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"19 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979519","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":"Correction: Cardiovascular diseases and depression: A meta-analysis and Mendelian randomization analysis.","authors":"Jun Zeng, Yuting Qiu, Chengying Yang, Xinrong Fan, Xiangyu Zhou, Chunxiang Zhang, Sui Zhu, Yang Long, Kenji Hashimoto, Lijia Chang, Yan Wei","doi":"10.1038/s41380-025-03049-2","DOIUrl":"https://doi.org/10.1038/s41380-025-03049-2","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079137","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":"Association between autism and dementia across generations: evidence from a family study of the Swedish population","authors":"Zheng Chang, Honghui Yao, Shihua Sun, Le Zhang, Shengxin Liu, Isabell Brikell, Brian M. D’Onofrio, Henrik Larsson, Paul Lichtenstein, Ralf Kuja-Halkola, Sara Hägg, Francesca Happé, Mark J. Taylor","doi":"10.1038/s41380-025-03045-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03045-6","url":null,"abstract":"<p>There is emerging evidence to suggest that autistic individuals are at an increased risk for cognitive decline or dementia. It is unknown whether this association is due to shared familial influences between autism and dementia. The main purpose of this study was, thus, to investigate the risk of dementia in relatives of autistic individuals. We conducted a family study based on linking Swedish registers. We identified all individuals born in Sweden from 1980–2013, followed until 2020, and clinical diagnoses of autism among these individuals. We linked these index individuals with their parents, grandparents, and aunts/uncles. The risk of dementia (including any type of dementia, Alzheimer’s disease, and other types of dementia) in relatives of autistic individuals was estimated using Cox proportional hazards models. Analyses were then stratified by sex of the relatives and intellectual disability in autistic individuals. Relatives of autistic individuals were at an increased risk of dementia. The risk was strongest in parents (hazards ratio [HR] = 1.36, 95% confidence intervals = 1.25–1.49), and weaker in grandparents (HR = 1.08, 1.06–1.10) and aunts/uncles (HR = 1.15, 0.96–1.38). Furthermore, there were indications of a stronger association between autism in index individuals and dementia in mothers (HR = 1.51, 1.29–1.77) compared to dementia in fathers (HR = 1.30, 1.16–1.45). There was only a small difference in relatives of autistic individuals with and without intellectual disability. Our results provide evidence of familial co-aggregation between autism and different types of dementia, and a potential genetic link. Future research now needs to clarify the risk of dementia in autistic individuals.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"43 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979454","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 history of metaphorical brain talk in psychiatry","authors":"Kenneth S. Kendler","doi":"10.1038/s41380-025-03053-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03053-6","url":null,"abstract":"<p>From the very beginnings of our field in the late 18th century, psychiatrists have engaged, often extensively, in “metaphorical brain talk” – rephrasing descriptions of mental processes in unconfirmed brain metaphors (e.g., “diseased working of the brain convolutions”). In the late 19th century, Kraepelin criticized the later developments of such approaches, termed “brain mythology” by the philosopher/psychiatrist Jaspers in 1913. In this essay, I review the history, meaning, and significance of this phenomenon and reach four conclusions. First, this trend has continued to the present day in metaphors such as the “broken brain” and the use of simplistic and empirically poorly supported explanations of psychiatric illness, such as depression being “due to an imbalance of serotonin in the brain.” Second, our language stems from the tension in our profession that seeks to be a part of medicine yet declares our main focus as treatment of the mental. We feel more comfortable with the reductionist approach of brain metaphors, which, even though at times self-deceptive, reinforce our commitment to and membership in a brain-based medical specialty. Third, metaphorical brain talk can also be seen as the “promissory note” of our profession, a pledge that the day will come when we can indeed explain accurately to ourselves and to our patients the brain basis of the psychiatric disorders from which they suffer. Finally, moving away from metaphorical brain talk would reflect an increasing maturity of both the research and clinical aspects of our profession.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"114 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945759","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":"Editorial Expression of Concern: Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia.","authors":"A Banerjee, H-Y Wang, K E Borgmann-Winter, M L MacDonald, H Kaprielian, A Stucky, J Kvasic, C Egbujo, R Ray, K Talbot, S E Hemby, S J Siegel, S E Arnold, P Sleiman, X Chang, H Hakonarson, R E Gur, C-G Hahn","doi":"10.1038/s41380-025-03050-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03050-9","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973049","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":"Deciphering the influence of socioeconomic status on brain structure: insights from Mendelian randomization","authors":"Charley Xia, Yuechen Lu, Zhuzhuoyu Zhou, Mattia Marchi, Hyeokmoon Kweon, Yuchen Ning, David C. M. Liewald, Emma L. Anderson, Philipp D. Koellinger, Simon R. Cox, Marco P. Boks, W. David Hill","doi":"10.1038/s41380-025-03047-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03047-4","url":null,"abstract":"<p>Socioeconomic status (SES) influences physical and mental health, however its relation with brain structure is less well documented. Here, we examine the role of SES on brain structure using Mendelian randomisation. First, we conduct a multivariate genome-wide association study of SES using educational attainment, household income, occupational prestige, and area-based social deprivation, with an effective sample size of <i>N</i> = 947,466. We identify 554 loci associated with SES and distil these loci into those that are common across those four traits. Second, using an independent sample of ~35,000 we provide evidence to suggest that SES is protective against white matter hyperintensities as a proportion of intracranial volume (WMHicv). Third, we find that differences in SES still afford a protective effect against WMHicv, independent of that made by cognitive ability. Our results suggest that SES is a modifiable risk factor, causal in the maintenance of cognitive ability in older-age.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940632","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":"Implications of neurogenesis in depression through BDNF: rodent models, regulatory pathways, gut microbiota, and potential therapy","authors":"Haijun Han, Jianhua Yao, Jinhan Wu, Shiqi Mao, Hongyi Pan, Lingling Qv, Guanqi Zhu, Juntian Ren, Yaning Yu, Feiyang Xuan, Linghui Zeng, Yunlong Ma, Zhongli Yang, Zhijing Zhu, Feng Zhu, Ming D. Li","doi":"10.1038/s41380-025-03044-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03044-7","url":null,"abstract":"<p>Major Depressive Disorder (MDD) is a prevalent psychiatric disorder with a profound impact on global health, necessitating a deeper understanding of its pathophysiology. This review synthesizes current evidence linking neurogenesis, particularly in the hippocampal region, with MDD. Accumulating data showed a significant reduction of neurogenesis in the hippocampal region of both MDD patients and various MDD rodent models. We highlight the role of brain-derived neurotrophic factor (BDNF) and its associated signaling pathways in regulating neurogenesis and depressive symptoms. Additionally, the influence of gut microbiota on the neurogenesis in depression is presented, offering a novel perspective on environmental modulation of neurogenesis. This review also underscores the potential antidepressant interventions targeting neurogenesis and BDNF’s regulation, such as therapeutic benefits of environmental enrichment, physical activity, and pharmacological agents in enhancing neurogenesis and alleviating depressive symptoms. Together, this systemic review provides a foundation for future research aiming at developing personalized treatments by targeting neurogenesis in MDD, potentially leading to novel biomarkers and therapeutic strategies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927272","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":"CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease","authors":"Maria Marchese, Sara Bernardi, Rachele Vivarelli, Stefano Doccini, Lorenzo Santucci, Asahi Ogi, Rosario Licitra, Jingjing Zang, Rabah Soliymani, Serena Mero, Stephan CF Neuhauss, Lea Ciarmoli, Giovanni Signore, Maciej M. Lalowski, Filippo M. Santorelli","doi":"10.1038/s41380-025-03043-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03043-8","url":null,"abstract":"<p>CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in the <i>CLN5</i> gene encoding the lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and lysosomal function. Limited knowledge of cellular mechanisms and unclear drug targets hinder translating this to children’s treatment, which remains symptomatic. We developed and characterized a new <i>cln5</i> knock-out zebrafish model that replicates key features and molecular signatures of the human disease. Loss of Cln5 function in vivo altered axonal growth of retinal ON-bipolar cells and disrupted calcium homeostasis in the cerebellum, revealing new disease features. Additionally, multi-omic analyses at different developmental stages revealed an impaired glucose metabolism as an original finding in NCL. A novel biomarker, PHGDH, was validated in zebrafish and human skin fibroblasts harboring pathogenic variants in <i>CLN5</i>, and in <i>CLN7</i>. We also tested metformin which improved the expression of PHGDH in patient-derived cells, and rescued zebrafish behavior. This work demonstrates the profound metabolic impact of CLN5 dysfunction, offering a promising avenue toward targeted therapies for juvenile dementia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"49 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930757","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":"Correction: Delta opioid receptor agonists activate PI3K-mTORC1 signaling in parvalbumin-positive interneurons in mouse infralimbic prefrontal cortex to exert acute antidepressant-like effects.","authors":"Toshinori Yoshioka, Daisuke Yamada, Akari Hagiwara, Keita Kajino, Keita Iio, Tsuyoshi Saitoh, Hiroshi Nagase, Akiyoshi Saitoh","doi":"10.1038/s41380-025-03046-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03046-5","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981850","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}