Molecular Psychiatry最新文献

{"title":"In utero exposure to methylphenidate, amphetamines and atomoxetine and offspring neurodevelopmental disorders – a population-based cohort study and meta-analysis","authors":"Kathrine Bang Madsen, Henrik Larsson, Charlotte Skoglund, Xiaoqin Liu, Trine Munk-Olsen, Veerle Bergink, Jeffrey H. Newcorn, Samuele Cortese, Paul Lichtenstein, Ralf Kuja-Halkola, Zheng Chang, Brian D’Onofrio, Per Hove Thomsen, Kari Klungsøyr, Isabell Brikell, Miguel Garcia-Argibay","doi":"10.1038/s41380-025-02968-4","DOIUrl":"https://doi.org/10.1038/s41380-025-02968-4","url":null,"abstract":"<p>The use of Attention-Deficit/Hyperactivity Disorder (ADHD) medications during pregnancy is increasing, raising concerns about potential long-term effects on offspring. This study investigates in utero exposure to methylphenidate, amphetamines and atomoxetine and risk of offspring neurodevelopmental disorders (NDDs). The population-based cohort study identified from Swedish registers included 861,650 children born by 572,731 mothers from 2008–2017. We categorized exposure based on redeemed medication during pregnancy and compared exposed children to those whose mothers discontinued medication before conception. Main outcomes were any NDD, including ADHD and autism spectrum disorder (ASD). Cox proportional hazards regression estimated hazard ratios (HRs), adjusting for maternal psychiatric and sociodemographic factors. Sensitivity analyses included stratifications by medication type, timing, and duration of exposure, and sibling comparisons. We also performed a meta-analysis combining data from the present study with those from a previous Danish study. Results showed no increased risk for any NDD (HR_adjusted 0.95, 95% CI 0.82–1.11), ADHD (HR_adjusted 0.92, 95% CI 0.78–1.08), or ASD (HR_adjusted 0.86, 95% CI 0.63–1.18). Sensitivity analyses showed consistent patterns of no increased risks across different exposure durations, medication types and between siblings. Meta-analyses further supported the findings (pooled HR for any NDD 1.00, 95% CI 0.83;1.20). Our study provides evidence that in utero exposure to ADHD medications does not increase the risk of long-term NDDs in offspring. This study replicates safety data for methylphenidate and extends it with new safety data on amphetamines and atomoxetine. These findings are crucial for informing clinical guidelines and helping healthcare providers and expectant mothers make informed decisions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"4 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723199","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":"Reduced attention to human eyes in autism-associated Shank3 mutant laboratory beagle dogs","authors":"Yumo Li, Qiandong Wang, Siqi Yuan, Tak Kwan Lam, Kun Guo, Yong Q. Zhang, Li Yi","doi":"10.1038/s41380-025-02965-7","DOIUrl":"https://doi.org/10.1038/s41380-025-02965-7","url":null,"abstract":"<p>Autistic individuals often exhibit reduced attention to faces and eyes, which may underlie their social difficulty. This study used eye-tracking techniques to explore visual attention towards faces in <i>Shank3</i> mutant laboratory beagle dogs, a model for autism, to identify parallels with human autism. We first assessed visual attention differences towards the eyes between <i>Shank3</i> mutant and wild-type (WT) laboratory beagles by presenting them with human and dog face images. Then, using the gaze cueing paradigm, we directed the dogs’ gaze towards the eyes and mouth and quantified their gaze shifts. Finally, we investigated the impact of oxytocin on eye-gaze behavior by comparing gaze patterns under pre-administration, vehicle, and oxytocin conditions while viewing human faces. We found that mutant dogs showed a reduced proportional viewing time of human eyes than WT dogs (<i>p</i> = 0.032), but no difference in proportional eye viewing time when viewing dog faces (<i>p</i> = 0.691). Mutant dogs shifted their gazes away from the human eyes more quickly than the mouth (<i>p</i> = 0.043), unlike WT dogs (<i>p</i> = 0.345), suggesting an active eye avoidance. Furthermore, exogenous oxytocin increased proportional viewing time on human eyes in mutant dogs than pre-administration and vehicle conditions (<i>p</i> = 0.022), suggesting a potential effect of oxytocin on social attention in autism. To our knowledge, this study is the first to report an eye avoidance phenotype in an animal model of autism. These findings contribute to our understanding of the mechanisms underlying social difficulties in autism and the development of supporting strategies for autism.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"21 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712776","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 neural pathway from the superior subpart of the medial habenula to the interpeduncular nucleus suppresses anxiety","authors":"Takehisa Handa, Taku Sugiyama, Tanvir Islam, Joshua P. Johansen, Yuchio Yanagawa, Thomas J. McHugh, Hitoshi Okamoto","doi":"10.1038/s41380-025-02964-8","DOIUrl":"https://doi.org/10.1038/s41380-025-02964-8","url":null,"abstract":"<p>The medial habenula (MHb) and its projection target, the interpeduncular nucleus (IPN), are highly conserved throughout vertebrate evolution. The MHb-IPN pathway connects the limbic system to the brainstem, consisting of subpathways that project in a topographically organized manner, and has been implicated in the regulation of fear and anxiety. Previous studies have revealed subregion-specific functions of the cholinergic ventral MHb and a substance P (SP)-positive (SP⁺) subpart of the dorsal MHb (dMHb). In contrast, the dMHb also contains another subpart, a SP-negative subpart known as the ‘superior part of MHb (MHbS)’. Although the MHbS has been characterized from various aspects, <i>e.g</i>. distinct c-Fos responses to stressful events and electrophysiological properties compared to other subregions, many of its physiological functions remain to be investigated. Here we found that dopamine receptor D3 (DRD3)-Cre mice enable the labeling of the IPN subregion that receives the MHbS projection. The Cre-expressing somata within the lateral subnucleus of the IPN (LIPN) were concentrated in its most lateral area, which we refer to as the ‘lateral subregion of the LIPN (lLIPN)’. This region is characterized by the absence of SP⁺ axons, in contrast to the medial subregion of the LIPN (mLIPN) innervated by the SP⁺ axons from the dorsal MHb. Chemogenetic activation and genetically induced synaptic silencing of the DRD3-Cre⁺ cells reduced and enhanced anxiety-like behavior, respectively. Moreover, c-Fos expression was increased in the lLIPN under an anxiogenic environment. These findings suggest that the MHbS-lLIPN pathway is activated under anxiogenic environments to counteract anxiety.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"59 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712778","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":"Targeting HINT1 to improve synaptic plasticity: toward loganin as a new antidepressant strategy","authors":"Congyuan Xia, Guoyan Zuo, Manni Wang, Yuming Wang, Yuxuan Guo, Yan Han, Honglin Xiang, Yungchi Cheng, Jiekun Xu, Jun He, Weiku Zhang","doi":"10.1038/s41380-025-02959-5","DOIUrl":"https://doi.org/10.1038/s41380-025-02959-5","url":null,"abstract":"<p>Histidine triad nucleotide-binding protein 1 (HINT1) is related to depression. However, the underlying mechanisms and whether HINT1 is a therapeutic target for depression remain unclear. In this study, we report that loganin, an antidepressant candidate from our previous research, directly targets HINT1 to alleviate depressive-like behaviors. Overexpression of HINT1 in the hippocampus induces depressive-like behaviors. Mechanistically, HINT1 hinders sigma-1 receptor (Sigma-1R) binding to N-methyl-D-aspartate receptor (NMDAR), promotes postsynaptic density protein (PSD95) binding to NMDAR, inhibits brain derived neurotrophic factor (BDNF) signaling, and impairs synaptic plasticity. The interaction between HINT1 and NMDAR is disturbed by loganin. The antidepressant-like effects of loganin are reversed by HINT1 overexpression, Sigma-1R inhibitor and tropomyosin kinase receptor B (TrkB) inhibitor. These results not only indicate that HINT1 induces depression via impairing synaptic plasticity but also provide a candidate targeting HINT1 for depression therapy.</p><figure><p>Zhang et al. reported that a natural compound, loganin, improves synaptic plasticity and reduces depressive-like behaviors via its direct target HINT1. Mechanistically, overexpressed HINT1 hinders NMDAR/Sigma-1R interactions and increases NMDAR/PSD95 interactions, and HINT1/NMDAR interactions are disrupted by loganin treatment.</p></figure>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"7 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695485","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 KCNQ potassium channel modulation on ventral tegmental area activity and connectivity in individuals with depression and anhedonia","authors":"Laurel S. Morris, Sara Costi, Sara Hameed, Katherine A. Collins, Emily R. Stern, Avijit Chowdhury, Carole Morel, Ramiro Salas, Dan V. Iosifescu, Ming-Hu Han, Sanjay J. Mathew, James W. Murrough","doi":"10.1038/s41380-025-02957-7","DOIUrl":"https://doi.org/10.1038/s41380-025-02957-7","url":null,"abstract":"<p>Up to half of individuals with depression do not respond to first-line treatments, possibly due to a lack of treatment interventions informed by neurobiology. A novel therapeutic approach for depression has recently emerged from translational work targeting aberrant activity of ventral tegmental area (VTA) dopamine neurons via modulation of the KCNQ voltage-gated potassium channels. In this study, individuals with major depressive disorder (MDD) with elevated anhedonia were randomized to five weeks of the KCNQ channel opener, ezogabine (up to 900 mg/day) or placebo. Participants completed functional MRI during a monetary anticipation task and resting-state at baseline and at end-of-treatment. The clinical results were reported previously. Here, we examined VTA activity during monetary anticipation and resting-state functional connectivity between the VTA and the ventromedial prefrontal cortex (mesocortical pathway) and ventral striatum (mesolimbic pathway) at baseline and end-of-treatment. Results indicated a significant drug-by-time interaction in VTA activation during anticipation (F_(1,34) = 4.36, <i>p</i> = 0.044), where VTA activation was reduced from pre-to-post ezogabine, compared to placebo. Mesocortical functional connectivity was also higher in depressed participants at baseline compared to a healthy control group (t₍₅₆₎ = 2.68, <i>p</i> = 0.01) and associated with VTA hyper-activity during task-based functional MRI at baseline (R = 0.352, <i>p</i> = 0.033). Mesocortical connectivity was also reduced from pre-to-post ezogabine, compared to placebo (significant drug-by-time interaction, F_(1,33) = 4.317, <i>p</i> = 0.046). Together this translational work is consistent with preclinical findings highlighting VTA hyper-activity in depression, and suggesting a mechanism of action for KCNQ channel openers in normalizing this hyper-activity in individuals with both depression and anhedonia.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"21 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703181","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":"Interleukin 18 and the brain: neuronal functions, neuronal survival and psycho-neuro-immunology during stress","authors":"Silvia Alboni, Fabio Tascedda, Akihito Uezato, Shuei Sugama, Zuxin Chen, Maria Cecilia Garibaldi Marcondes, Bruno Conti","doi":"10.1038/s41380-025-02951-z","DOIUrl":"https://doi.org/10.1038/s41380-025-02951-z","url":null,"abstract":"<p>Interleukin 18 (IL-18) is a pleiotropic cytokine that regulates peripheral innate and adaptive immune response and is also expressed in the brain. Here, we summarize the current knowledge on the biology of IL-18 in the brain and the efforts to determine its significance concerning neurological and psychiatric conditions. The picture that emerges is that of a heavily regulated molecule that can contribute to neuroinflammatory-mediated neuronal survival but can also serve as a neuromodulator that affects behaviour. We also summarize evidence showing how the brain can control the synthesis of peripheral IL-18 during stress by hormonal and neuronal signalling, regulating tissue-specific promoter usage. We discuss how this may represent one of the mechanisms by which the brain affects immune functions and what its implications are when considering IL-18 as a biomarker of psychiatric conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"27 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675221","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":"Generalizability of clinical prediction models in mental health","authors":"Maike Richter, Daniel Emden, Ramona Leenings, Nils R. Winter, Rafael Mikolajczyk, Janka Massag, Esther Zwiky, Tiana Borgers, Ronny Redlich, Nikolaos Koutsouleris, Renata Falguera, Sharmili Edwin Thanarajah, Frank Padberg, Matthias A. Reinhard, Mitja D. Back, Nexhmedin Morina, Ulrike Buhlmann, Tilo Kircher, Udo Dannlowski, Tim Hahn, Nils Opel","doi":"10.1038/s41380-025-02950-0","DOIUrl":"https://doi.org/10.1038/s41380-025-02950-0","url":null,"abstract":"<p>Concerns about the generalizability of machine learning models in mental health arise, partly due to sampling effects and data disparities between research cohorts and real-world populations. We aimed to investigate whether a machine learning model trained solely on easily accessible and low-cost clinical data can predict depressive symptom severity in unseen, independent datasets from various research and real-world clinical contexts. This observational multi-cohort study included 3021 participants (62.03% females, <i>M</i>_Age = 36.27 years, range 15–81) from ten European research and clinical settings, all diagnosed with an affective disorder. We firstly compared research and real-world inpatients from the same treatment center using 76 clinical and sociodemographic variables. An elastic net algorithm with ten-fold cross-validation was then applied to develop a sparse machine learning model for predicting depression severity based on the top five features (global functioning, extraversion, neuroticism, emotional abuse in childhood, and somatization). Model generalizability was tested across nine external samples. The model reliably predicted depression severity across all samples (<i>r</i> = 0.60, <i>SD</i> = 0.089, <i>p</i> &lt; 0.0001) and in each individual external sample, ranging in performance from <i>r</i> = 0.48 in a real-world general population sample to <i>r</i> = 0.73 in real-world inpatients. These results suggest that machine learning models trained on sparse clinical data have the potential to predict illness severity across diverse settings, offering insights that could inform the development of more generalizable tools for use in routine psychiatric data analysis.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"9 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653592","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":"Large-scale plasma proteomics uncovers novel targets linking ambient air pollution and depression","authors":"Chuyu Pan, Xin Qi, Xuena Yang, Bolun Cheng, Shiqiang Cheng, Li Liu, Peilin Meng, Dan He, Wenming Wei, Jingni Hui, Boyue Zhao, Yan Wen, Yumeng Jia, Huan Liu, Feng Zhang","doi":"10.1038/s41380-025-02953-x","DOIUrl":"https://doi.org/10.1038/s41380-025-02953-x","url":null,"abstract":"<p>Despite the growing recognition of association between air pollution and increased risk of depression, the intricate biological mechanisms underlying it remains unclear. In this study, a total of 1463 plasma proteins were measured by the Olink Explore platform for 50,553 participants in a large prospective cohort. Four air pollutants were assessed using land-use regression models: particulate matter with aerodynamic diameter ≤ 2.5μm (PM_2.5), particulate matter with aerodynamic diameter &gt; 2.5μm and ≤ 10μm (PM_2.5–10), nitrogen dioxide (NO₂), and nitric oxide (NO). The air pollution index was calculated using principal components analysis to assess joint exposure to air pollution. Logistic regression and Cox proportional hazards regression analyses were respectively used to explore the impact of the interaction between air pollution exposure and plasma proteins on the prevalence and incidence of depression. Functional enrichment analysis and drug prediction analysis were conducted to explore the biological mechanisms and drugs associated with identified plasma proteins with interaction effects. Logistic regression analysis detected seven significant air pollutant and plasma protein interactions for the prevalence of depression, such as CDHR5 vs. PM_2.5 (OR: 0.58; 95% CI: 0.48–0.71), TNFRSF13C vs. NO (OR :0.70, 95% CI: 0.58–0.84) and ICAM5 vs. air pollution index (OR: 1.38, 95% CI: 1.17–1.63). Two significant interactions were identified for the incidence of depression: CDHR5 vs. PM_2.5 (HR: 0.62, 95% CI: 0.50–0.76) and HSD11B1 vs. PM_2.5 (HR: 1.48, 95% CI: 1.22–1.81). The plasma proteins that interacted with air pollutants were enriched in various Gene Ontology terms and pathways involving immunity, endocrine, inflammation, neurological function and metabolism, such as neuroinflammatory response, neuron projection guidance, regulation of lymphocyte mediated immunity, steroid biosynthetic process and lipid digestion. We also found that these proteins interacted with multiple drugs, such as risperidone, olanzapine and progesterone. This study identified novel targets linking ambient air pollution and depression, providing the insights for biological mechanisms of air pollution affecting the risk of depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"5 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661441","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":"Recapitulation and reversal of neuropsychiatric phenotypes in a mouse model of human endogenous retrovirus type W expression","authors":"Felisa Herrero, Celine Heeb, Michelle Meier, Han-Yu Lin, Flavia S. Mueller, Sina M. Schalbetter, Joel Gruchot, Ulrike Weber-Stadlbauer, Tina Notter, Hervé Perron, Patrick Küry, Urs Meyer","doi":"10.1038/s41380-025-02955-9","DOIUrl":"https://doi.org/10.1038/s41380-025-02955-9","url":null,"abstract":"<p>Human endogenous retroviruses (HERVs) are inherited genetic elements derived from exogenous retroviral infections occurring throughout evolution. Accumulating evidence implicates increased expression of HERV type W envelope (HERV-W ENV) in psychiatric and neurodevelopmental disorders. To gain more mechanistic insights into the neurobiological disease pathways affected by HERV-W ENV expression, we took advantage of a mouse model that recapitulates the expression of the human-specific HERV-W ENV protein. Behavioral and cognitive phenotyping of transgenic (TG) mice expressing HERV-W ENV and wild-type (WT) controls showed that expression of this retroviral envelope caused deficits in numerous functional domains, including repetitive behavior, social and object recognition memory, and sensorimotor gating. Genome-wide RNA sequencing of hippocampal tissue demonstrated that transgenic expression of HERV-W ENV led to transcriptomic alterations that are highly relevant for psychiatric and neurodevelopmental disorders, cognitive functions, and synaptic development. Differential gene expression in TG mice encompassed a downregulation of several genes associated with schizophrenia and autism spectrum disorder, including <i>Setd1a</i>, <i>Cacna1g</i>, <i>Ank3</i>, and <i>Shank3</i>, as well as a downregulation of histone methyltransferase genes that belong to the Set1-like histone H3 lysine 4 (H3K4) methyltransferase family (<i>Kmt2a</i>, <i>Kmt2b</i> and <i>Kmt2d</i>). Concomitant to the latter, HERV-W ENV mice displayed increased enzymatic activity of lysine-specific demethylase-1 (LSD1), increased H3K4 mono-methylation, and decreased H3K4 di- and tri-methylation in the hippocampus. Importantly, pharmacological inhibition of LSD1 through oral ORY-1001 treatment normalized abnormal H3K4 methylation and rescued the behavioral and cognitive deficits in HERV-W ENV mice. In conclusion, our study suggests that the expression of HERV-W ENV has the capacity to disrupt various behavioral and cognitive functions and to alter the brain transcriptome in a manner that is highly relevant to neurodevelopmental and psychiatric disorders. Moreover, our study identified epigenetic pathways that may offer avenues for pharmacological interventions against behavioral and cognitive deficits induced by increased HERW-W expression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"15 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640857","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":"Neural mechanisms underlying reduced nocifensive sensitivity in autism-associated Shank3 mutant dogs","authors":"Qi Shi, Baolong Ren, Xuejing Lu, Libo Zhang, Liang Wu, Li Hu, Yong Q. Zhang","doi":"10.1038/s41380-025-02952-y","DOIUrl":"https://doi.org/10.1038/s41380-025-02952-y","url":null,"abstract":"<p>Autistic individuals carrying mutations in <i>SHANK3</i> (encoding a synaptic scaffolding protein) have been consistently reported to exhibit reduced pain sensitivity. However, the neural mechanisms underlying impaired pain processing remain unclear. To investigate the role of <i>SHANK3</i> in pain processing, we conducted behavioral, electrophysiological, and pharmacological tests upon nociceptive stimulation in a <i>Shank3</i> mutant dog model. Behaviorally, <i>Shank3</i> mutant dogs showed reduced nocifensive sensitivity compared to wild-type (WT) dogs. Electrophysiologically, <i>Shank3</i> mutant dogs exhibited reduced neural responses elicited by the activations of both Aδ- and C-fiber nociceptors. Additionally, <i>Shank3</i> mutants showed a lower level of aperiodic exponents, which serve as a marker for the excitatory-inhibitory balance of neural activity. The aperiodic exponents mediated the relationship between genotype and nocifensive sensitivity as well as between genotype and neural responses elicited by nociceptive stimuli. Pharmacologically, the reduced nocifensive sensitivity and atypical excitatory-inhibitory balance were rescued by a GABA_AR antagonist pentylenetetrazole. These findings highlight the critical role of <i>Shank3</i> in pain processing and suggest that an impaired excitatory-inhibitory balance may be responsible for the reduced nocifensive reactivity in autism.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"42 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635689","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}