Molecular Psychiatry最新文献

{"title":"Association between FDG- and TSPO-PET signals across human and animal studies investigating neurodegenerative conditions: a systematic review","authors":"Luiza S. Machado, Pedro Vidor, Lavínia Perquim, Christian Limberger, Leonardo Machado, Andréia Rocha, Carolina Soares, Nesrine Rahmouni, Wagner S. Brum, Bruna Bellaver, Pamela C. L. Ferreira, Wyllians V. Borelli, Jaderson C. da Costa, Maura Malpetti, Tharick A. Pascoal, Diogo O. Souza, Paul Edison, Kaj Blennow, Henrik Zetterberg, Nicholas J. Ashton, Andrea L. Benedet, Alberto Serrano-Pozo, Pedro Rosa-Neto, Eduardo R. Zimmer","doi":"10.1038/s41380-025-03160-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03160-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Fluorodeoxyglucose (FDG)-PET hypometabolism is considered a biomarker of neurodegeneration. However, recent evidence revealed that glial cells contribute to the FDG-PET signal. In this context, microglial changes have been evaluated with 18-kDa translocator protein (TSPO)-PET radiopharmaceuticals. While several studies have concomitantly conducted FDG- and TSPO-PET imaging, their associations remain controversial.</p><h3 data-test=\"abstract-sub-heading\">Objective</h3><p>We systematically revised multi-tracer preclinical and clinical studies using FDG- and TSPO-PET to investigate neurodegenerative conditions.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>From 401 studies, 14 preclinical studies, 7 clinical studies and 1 study including both met the inclusion criteria. The preclinical studies included mouse models of amyloid, tau, and neurotoxins, whereas the clinical studies investigated Alzheimer’s disease, Parkinson’s disease and frontotemporal lobar degeneration. Most clinical studies found a negative association between FDG- and TSPO-PET signals, whereas animal studies showed mixed results being highly dependent on the radiotracer used.</p><h3 data-test=\"abstract-sub-heading\">Discussion</h3><p>Our findings support the connection between glial and metabolic changes in the brain while highlighting glial heterogeneity between species and the specificities of TSPO-PET radiotracers. To better understand the dynamic associations between FDG- and TSPO-PET, it is essential to conduct longitudinal studies during the early stages of neurodegenerative disorders, along with the use of novel mouse models that more accurately represent these conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"40 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987415","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":"Reply to Gattuso et al.: “Comments on ‘Striking long-term beneficial effects of single-dose psilocybin and psychedelic mushroom extract in the SAPAP3 rodent model of OCD-like excessive self-grooming’ by Brownstien et al. (2024)”","authors":"Michal Brownstien, Michal Lazar, Alexander Botvinnik, Ilana Pogodin, Tzuri Lifschytz, Bernard Lerer","doi":"10.1038/s41380-025-03173-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03173-z","url":null,"abstract":"&lt;p&gt;We thank Gattuso and colleagues [1] for their kind comments about our paper [2]. However, we wish to note several inaccuracies in statements made about our research and respond to some of their observations:&lt;/p&gt;&lt;ol&gt;\u0000&lt;li&gt;\u0000&lt;span&gt;1)&lt;/span&gt;\u0000&lt;p&gt;The contention that we did not take sex into account in our analyses is incorrect. On the contrary, we compared self-grooming and head-body twitches in male and female SAPAP3-KO mice as the first step in our data analysis. We then analyzed the effect of psilocybin treatment on these variables in males and females separately. The results are shown in Supplementary Tables 1 and 2. There were no differences between males and females at baseline, nor in the effect of psilocybin treatment. Therefore, males and females were combined for further analyses. Sex was also taken into account in our analysis of the behavioral tests.&lt;/p&gt;\u0000&lt;/li&gt;\u0000&lt;li&gt;\u0000&lt;span&gt;2)&lt;/span&gt;\u0000&lt;p&gt;Our study was designed and executed as would a clinical trial in patients. In patients with OCD and other disorders, clinical trials do not include an arm in which individuals who do not suffer from the disorder receive the treatment. Therefore, the non-inclusion of such an arm in our study cannot be seen as a shortcoming. Furthermore, compulsive behaviors are, frequently, normal behaviors carried out in an exaggerated way. This is true of the excessive self-grooming of SAPAP3-KO mice. It is of interest that in their own paper on the effect of psilocybin on self-grooming, Gattusso et al. [3] found evidence for a reduction of self-grooming in wild type mice administered psilocybin. However, the absence of a wild type group treated with psilocybin does not detract from the validity of our findings. In the same way, finding that fluoxetine reduces the frequency of hand-washing in individuals without OCD does not in any way detract from a finding that fluoxetine reduces compulsive handwashing.&lt;/p&gt;\u0000&lt;/li&gt;\u0000&lt;li&gt;\u0000&lt;span&gt;3)&lt;/span&gt;\u0000&lt;p&gt;Gattuso et al. [1] note that excessive self-grooming increased substantially over the 42 days of our study in SAPAP3-KO mice. A progressive increase in self-grooming after the age of 6 months is by no means idiosyncratic as Gattuso et al. [3] appear to imply and has been noted by other authors. Thus, Glorie et al. [4] examined SAPAP3-KO mice from 6–9 months and reported an “increase in grooming duration with ageing.” Similarly, Manning et al. [5] reported a progressive increase in self-grooming up to the age of 8 months.&lt;/p&gt;\u0000&lt;/li&gt;\u0000&lt;li&gt;\u0000&lt;span&gt;4)&lt;/span&gt;\u0000&lt;p&gt;Comments made by Gattuso et al. [1] regarding our study, rest significantly on the findings of their own study on the effect of psilocybin on self-grooming in SAPAP3-KO mice [3]. We are gratified that this work replicated our findings reported in Brownstien et al. [2]. However, we note that in their study Gattuso et al. [3] performed a very limited assessment of self-grooming, quantifying the behavior for only 10 min following 10-min acclimatization. In our study [2] we scored self-grooming","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"66 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930221","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":"Heavy adolescent drinking makes the adult brain more vulnerable to ethanol by permanently altering the age-dependent interplay between alcohol, GIRK channels and activin","authors":"Sophia Stürzenberger, Nicolas Bülow, Liubov S. Kalinichenko, Rebecca Licha, Volker Eulenburg, Marc Dahlmanns, Christian P. Müller, Fang Zheng, Christian Alzheimer","doi":"10.1038/s41380-025-03210-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03210-x","url":null,"abstract":"<p>Adolescent binge drinking is a risk behavior associated with the development of neuropsychiatric disorders later in life, but the pathophysiological mechanisms rendering the adolescent brain vulnerable to the long-term consequences of heavy alcohol consumption are only partially understood. Here, we used a mouse model of adolescent binge drinking and focussed on G protein-gated inwardly rectifying potassium (GIRK) channels which are a molecular target of both ethanol and the pluripotent growth and differentiation factor activin A. In whole-cell recordings from dentate gyrus granule cells in brain slices from alcohol-naive mice, we found a striking reversal of the effect of activin A on ethanol-evoked GIRK current as the mice matured: Whereas activin A reduced the ethanol response in cells from adult mice, the already lower ethanol threshold in cells from young mice was brought down even further by activin A. In cells from adult mice with binge drinking-like experience in their youth, the reversal of the activin effect on ethanol-evoked GIRK current with maturation was abrogated, thereby perpetuating the adolescent phenotype of activin-boosted ethanol sensitivity into adulthood. Underscoring the translational significance of an aberrantly enhanced GIRK current response to ethanol, the GABA_B receptor agonist baclofen, which is used as an “off-label” prescription against alcohol use disorders, suppressed the permanently enhanced GIRK response to ethanol after heavy adolescent drinking.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"19 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930222","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":"Reviewing vascular influences on neuronal migration, cortical development, and neurodevelopmental disorders: focus on autism, ADHD and schizophrenia","authors":"Lalit K. Ahirwar, Spiros L. Blackburn, Devin W. McBride, Peeyush Kumar. T","doi":"10.1038/s41380-025-03200-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03200-z","url":null,"abstract":"<p>During cortical development, newly born neurons migrate radially or tangentially from their origin to expand the cortex. Simultaneously, neuron-derived factors support angiogenesis, and an elaborate network of blood cerebral vessels develops in the cortex. Traditionally, blood cerebral vessels were considered to support the growing cortex or migrating neurons by providing nutrients and oxygen. However, recent studies have shed light on Endothelial cells’ influence on cortical development; they guide neuronal migration by providing molecular cues and structural support. Here, we review the current understanding of how CNS cerebral vessels support neurogenesis, neuronal migration, and the formation of the six-layer cortical structure during development. Additionally, we explore current knowledge regarding the vascular role in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"141 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930223","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 phenome-wide association and Mendelian randomization study for suicide attempt within UK Biobank","authors":"Meiyan Huang, Xiaoling Zhang, Xiumei Chen, Xinyue Zhang, Bingxin Zhao, Chao Huang, Ting Tian, Chuang Li, Qianjin Feng, Wenliang Pan","doi":"10.1038/s41380-025-03214-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03214-7","url":null,"abstract":"<p>Uncertainties persist in the neurological and behavioral risk factors for suicide attempt (SA) due to a lack of data covering multiple phenotypes. Here, the polygenic risk scores (PRSs) for SA samples within the UK Biobank (<i>N</i> = 40,369) were estimated using non-overlapping Psychiatric Genomics Consortium datasets as a reference. A total of 70 PRS-associated phenotypes encompassing discovered and never-reported phenotypes were identified, thereby facilitating applications in SA identification (area under the curve of 84%). Different with the existing observational studies, the causal effects between brain and SA were explored. Mendelian randomization supported a potential causal effect of right hippocampal gray matter volume on SA, whereas SA had a reverse causal effect on the VI cerebellum. After controlling for the effects of psychiatric disorders, the right hippocampus still had an independent causal effect on SA. These findings provide multi-perspective evidence for early understanding and identification of SA and shed new lights for causal inference between brain and SA.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"42 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928604","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":"Cell membrane cholesterol affects serotonin transporter efflux due to altered transporter oligomerization","authors":"Deborah Rudin, Dino Luethi, Marco Niello, Jae-Won Yang, Isabella Burger, Walter Sandtner, Ruth Birner-Gruenberger, Gerhard J. Schütz, Harald H. Sitte","doi":"10.1038/s41380-025-03201-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03201-y","url":null,"abstract":"<p>The human monoamine transporters (MATs) for serotonin (SERT), dopamine (DAT), and norepinephrine (NET) play a key role in neurotransmission by transporting neurotransmitters from the synaptic cleft back into the neuron. MATs are embedded in the cell membrane’s lipid bilayer, encompassing cholesterol, phospholipids, and sphingolipids as main components. Membrane cholesterol association has been shown for all MATs impacting transporter conformation, substrate affinity, transport velocity, and turnover rates. In the present study, we compared the regulatory impact of cholesterol on the uptake and efflux function, binding affinity, and transporter oligomerization across all three MATs. We observed that cholesterol depletion impairs transporter-mediated uptake in human transporter-transfected HEK293 cells and reduces the binding affinity of all MATs. Electrophysiological investigations in SERT-expressing cells revealed that cholesterol alterations affect the transition of the transporter from the outward to the inward-facing conformation in the presence of substrate. Upon cholesterol depletion, FRET imaging and single molecule microscopy studies indicated altered oligomerization behavior exclusively for SERT. Interestingly, reduction of membrane cholesterol selectively increased amphetamine-induced efflux via SERT, while efflux via DAT and NET was reduced. This effect was diminished in a mutant with reduced PIP₂ binding capacity. Hence, the increased efflux at SERT due to cholesterol depletion appears to depend on the ability of PIP₂ to bind to SERT. Thus, we hypothesize that the interaction profile between cholesterol and MATs may fine-tune the transporter functionality and influence MAT-dependent disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930225","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":"Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice","authors":"Donn A. Van Deren, Ben Xu, Naveen Nagarajan, Anne M. Boulet, Shuhua Zhang, Mario R. Capecchi","doi":"10.1038/s41380-025-03190-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03190-y","url":null,"abstract":"<p>Disruption of the <i>Hoxb8</i> gene results in chronic anxiety and pathological overgrooming in mice. Using bilateral intracerebral cell transplantation, we demonstrate that mutant <i>Hoxb8</i> microglia are causative for both behaviors. Mice contain two microglia lineages, <i>Hoxb8</i> and non-<i>Hoxb8</i> microglia. We proposed that the two lineages work as a binary system, in opposition to each other with <i>Hoxb8</i> microglia functioning to reduce anxiety and grooming (function as brakes), whereas non-<i>Hoxb8</i> microglia increase the levels of both behaviors (function as accelerators). This model makes a strong, unexpected prediction: mice containing only wild-type canonical non-<i>Hoxb8</i> microglia should exhibit pathological levels of grooming and anxiety. We demonstrate that this is the case, providing strong support for both microglia functioning as a binary system and for the ‘Accelerator/Brake’ model. Since mice containing only non-<i>Hoxb8</i> microglia represent mice with a loss of <i>Hoxb8</i> function due to the absence of <i>Hoxb8</i> microglia, the more intensive pathology associated with <i>Hoxb8</i> mutant mice must reflect that mutant mice have both gain and loss of function components. We identify and quantify the relative contribution of each component.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"96 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930224","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":"Epigenetic, ribosomal, and immune dysregulation in paediatric acute-onset neuropsychiatric syndrome","authors":"Velda X. Han, Sarah Alshammery, Brooke A. Keating, Brian S. Gloss, Markus J. Hofer, Mark E. Graham, Nader Aryamanesh, Lee L. Marshall, Songyi Yuan, Emma Maple-Brown, Jingya Yan, Sushil Bandodkar, Kavitha Kothur, Hiroya Nishida, Hannah Jones, Erica Tsang, Xianzhong Lau, Ruwani Dissanayake, Iain Perkes, Shekeeb S. Mohammad, Fabienne Brilot, Wendy Gold, Shrujna Patel, Russell C. Dale","doi":"10.1038/s41380-025-03127-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03127-5","url":null,"abstract":"<p>Paediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterised by abrupt onset obsessive compulsive disorder and regression in neurodevelopmental skills, triggered by infection or stress. Whether PANS is a distinct entity or part of a neurodevelopmental spectrum is uncertain, and its pathophysiology remains unclear. We show that children with PANS (n = 32) and other non-PANS (n = 68) neurodevelopmental disorders (total n = 100) have higher reported early childhood infections and a loss of previously acquired developmental skills compared to neurotypical controls (n = 58). Children with PANS have normal routine immune testing, however bulk RNA-sequencing (PANS n = 20 vs controls n = 15) revealed upregulated pathways in ribosomal biogenesis and RNA methyltransferases, and downregulated pathways in diverse cellular functions such as mitochondrial activity, cell signalling, endocytosis, and immune responses. Single-cell RNA-sequencing (PANS n = 2 vs controls n = 2) confirmed these findings but showed heterogeneity across immune cell types. Toll-like receptor stimulation assay using peripheral blood mononuclear cells revealed reduced TNF and interleukin-6 responses in PANS patients (n = 7) compared to controls (n = 7). RNA sequencing before and after intravenous immunoglobulin treatment in PANS patients (n = 9 vs controls n = 10) revealed reversal of the dysregulated ribosomal, epigenetic, and cell signaling pathways. Given the central role of the immune system in synaptic pruning and neurodevelopment, these insights provide rationale for novel epigenetic and immune modulating therapies to optimize neurodevelopmental trajectories and minimize neuropsychiatric impairment in PANS.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"27 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919056","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":"Loss of Necdin causes social deficit and aberrant synaptic function through destabilization of SynGAP","authors":"Xiangyu Li, Ibrahim Bader, Xin Li, Renbin Lu, Dengfeng Liu, Zhiheng Chen, Suixin Deng, Yousheng Shu, Huadie Liu, Jing Zhang, Jia-Da Li","doi":"10.1038/s41380-025-03187-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03187-7","url":null,"abstract":"<p>The Ras GTPase-activating protein SynGAP interacts with PSD95 to regulate synaptic morphology and function at the postsynaptic density in neurons. Haploinsufficiency of <i>SYNGAP1</i> has been linked to autism spectrum disorders (ASD) and intellectual disability (ID). While transcriptional and translational regulation of SYNGAP1 has been extensively explored, the mechanisms governing its protein homeostasis remain largely elusive. In this study, we discovered that Necdin, a protein linked to Prader-Willi syndrome (PWS), interacts with SynGAP and regulates its stability through the SGT1-HSP90 chaperone machinery; notably, depletion of Necdin results in decreased SynGAP protein levels in mice. Loss of Necdin lead to impaired sociability, accompanied by an increased number of dendritic spines and a higher proportion of mature spines in pyramidal neurons of the medial prefrontal cortex (mPFC) in mice. Electrophysiological recordings revealed elevated frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) and reduced amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in these neurons. Targeted viral overexpression of <i>Syngap1</i> in the mPFC of Necdin-deficient mice rescued the deficits in sociability, synaptic function, and dendritic spine morphology. Collectively, our findings reveal Necdin as a key regulator of SynGAP protein homeostasis and highlight the contribution of post-translational regulation in the pathogenesis of ASD.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"26 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919113","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":"Effects of esketamine on electrophysiology and metabolic reprogramming in brain organoids: insights into antidepressant mechanisms","authors":"Mengjie Li, Wen Duan, Xiaoyan Hao, Shuangjie Li, Chen Wang, Yuanyuan Liang, Zhengwei Hu, Dongrui Ma, Mengnan Guo, Chunyan Zuo, Zhiyun Wang, Yanmei Feng, Chenwei Hao, Shasha Qi, Yuemeng Sun, Mibo Tang, Chengyuan Mao, Kenji Hashimoto, Yuming Xu, Junliang Yuan, Jianjun Yang, Changhe Shi","doi":"10.1038/s41380-025-03198-4","DOIUrl":"https://doi.org/10.1038/s41380-025-03198-4","url":null,"abstract":"<p>Esketamine, commonly used to treat treatment-resistant depression, has pharmacological mechanisms that remain incompletely understood. Brain organoids offer a human-relevant platform for investigating the cellular and molecular effects of drugs. In this study, we investigated the effects of esketamine on the electrophysiology and metabolism of brain organoids derived from iPSCs of healthy control subjects and depressed patients. Continuous monitoring revealed that esketamine treatment significantly decreased both the frequency and amplitude of action potentials, with the most pronounced reduction occurring within 4 h. High concentrations (1.5 mg/L) produced a stronger inhibitory effect, while organoids treated with a low concentration (0.25 mg/L) showed a recovery in action potential frequency after one week, although levels remained below pre-treatment values—a recovery not observed in the high-concentration group. Single-cell RNA sequencing demonstrated that esketamine modulated energy metabolism and induced metabolic reprogramming in a concentration- and time-dependent manner. Furthermore, by inhibiting oxidative phosphorylation and glycolysis separately and assessing cytosolic Ca²⁺ levels, we found that esketamine may regulate NMDAR activity and electrophysiology through energy metabolism pathways. These findings reveal a potential mechanism for esketamine’s effects and offer new insights for clinical treatment strategies.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"23 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919112","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}