Biological Psychiatry最新文献

{"title":"Inhibitory control and error processing in Obsessive-Compulsive Disorder: A mega-analysis of task-based fMRI data by the ENIGMA-OCD consortium","authors":"Nadža Džinalija,Odile A. van den Heuvel,H. Blair Simpson,Iliyan Ivanov,Ana Araújo,Srinivas Balachander,Jan Beucke,Daniel Brandeis,Silvia Brem,Willem Bruin,Jan Buitelaar,Miguel Castelo-Branco,Sunah Choi,Goi Khia Eng,Sophie M.D.D. Fitzsimmons,Lydia Fortea,Miquel A. Fullana,Rosa Grützmann,Bjarne Hansen,Chaim Huijser,Niels T. de Joode,Norbert Kathmann,Christian Kaufmann,Minah Kim,Kathrin Koch,Jun Soo Kwon,Jie Xin Lim,Ignacio Martinez-Zalacain,Jose M. Menchon,Laurens A. van de Mortel,Janardhanan C. Narayanaswamy,Olga Therese Ousdal,Tjardo S. Postma,Daniela Rodriguez-Manrique,Daan van Rooij,Venkataram Shivakumar,Carles Soriano-Mas,Emily R. Stern,Sophia I. Thomopoulos,Anders L. Thorsen,Enric Vilajosana,Susanne Walitza,Lea Waller,Ysbrand D. van der Werf,Guido van Wingen,Stella J. de Wit,Pino Alonso,Isabel Catarina Duarte,Kristen Hagen,Tobias U. Hauser,Taekwan Kim,Gerd Kvale,Y.C.Janardhan Reddy,Cinto Segalàs,Ganesan Venkatasubramanian,Dan J. Stein,Paul M. Thompson,Chris Vriend,Ilya M. Veer","doi":"10.1016/j.biopsych.2026.09.021","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.021","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"19 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088962","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":"Maternal immune activation influences social behavior development in a nonhuman primate model","authors":"Josephine A. Hubbard,Shuai Chen,Ana-Maria Iosif,Amy M. Ryan,Takeshi Murai,Casey E. Hogrefe,Tyler A. Lesh,Jason Smucny,Richard J. Maddock,Cynthia M. Schumann,Timothy D. Hanks,Judy Van de Water,A. Kimberley McAllister,Cameron S. Carter,Melissa D. Bauman","doi":"10.1016/j.biopsych.2026.09.023","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.023","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"13 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088960","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 ventral hippocampus-prefrontal circuit mediates the pro-extinction effects of adult hippocampal neurogenesis on contextual fear.","authors":"Barbara Planchez, Mohamed-Lyès Kaci, Marc Legrand, Yuki Sakai, Pauline Mériau, Laurane Pena, Lea Morel, Salomé Picquet, Ambre Frerot, Bruno Brizard, Anne-Marie Le Guisquet, Eva Ploux, René Hen, Alexandre Surget, Catherine Belzung","doi":"10.1016/j.biopsych.2026.09.017","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.017","url":null,"abstract":"<p><strong>Background: </strong>Adult hippocampal neurogenesis (AHN) contributes to hippocampal functions including contextual information processing and stress responses. Inhibiting AHN increases vulnerability to stress and hinders effects of therapeutic interventions for stress-related disorders, especially post-traumatic stress disorder (PTSD) characterized by maladaptive fear response to context, suggesting that promoting AHN may offer promising strategies. We therefore aimed to test whether experimentally enhancing AHN protects against persistent contextual fear memory and examine the underlying neural circuits.</p><p><strong>Methods: </strong>Using inducible Cre-dependent iBax male mice, we enhanced AHN via tamoxifen pretreatment prior to a high-intensity contextual fear conditioning (footshocks, 1.5mA, 2×2s). We assessed defensive responses to both the conditioning context and a conditioning-associated object, together with spatial memory controls, and combined retrograde labeling with projection-specific optogenetic inhibition.</p><p><strong>Results: </strong>AHN enhancement reduced the persistence of defensive responses to fear context: accelerating within-session decline of freezing and improving next-day extinction recall, while sparing other hippocampal-dependent memory. Circuit analyses revealed increased recruitment of a ventral hippocampus-prefrontal (infralimbic) cortex pathway in AHN-enhanced mice. Critically, optogenetic inhibition of this projection did not impair extinction per se but selectively abolished the pro-extinction effects induced by AHN enhancement; an effect not reproduced by inhibiting the projection to basolateral amygdala.</p><p><strong>Conclusions: </strong>Ventral hippocampal input to the prefrontal cortex is not required for baseline extinction but is necessary to mediate the facilitating effects of enhanced AHN on contextual fear extinction in male mice. These findings identify a circuit mechanism through which adult neurogenesis constrains the persistence of contextual fear and promotes adaptive fear regulation.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073419","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":"Ketamine Alters Tuning of Neural and Behavioral Spatial Working Memory Precision.","authors":"Masih Rahmati, Flora Moujaes, Nina Purg Suljic, Jie Lisa Ji, Lucie Berkovitch, Kangjoo Lee, Clara Fonteneau, Charles H Schleifer, Brendan D Adkinson, Aleksandar Savic, Nicole Santamauro, Zailyn Tamayo, Caroline Diehl, Antonija Kolobaric, Morgan Flynn, Terry Camarro, Clayton E Curtis, Grega Repovš, Sarah K Fineberg, Peter T Morgan, Katrin H Preller, John H Krystal, John D Murray, Youngsun T Cho, Alan Anticevic","doi":"10.1016/j.biopsych.2026.09.016","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.016","url":null,"abstract":"<p><strong>Background: </strong>Working memory (WM) is a key element of cognition that depends on accurate internal representation of stimuli and often impaired in psychiatric disorders, including schizophrenia. Prior human neuropharmacological studies with ketamine suggest that glutamate N-methyl-D-aspartate receptors (NMDARs) are critical for spatial WM (sWM), with NMDAR antagonism attenuating task-evoked neural activation and reducing WM accuracy. Animal studies, at the cellular level, and cortical microcircuit models hypothesize that NMDAR antagonism impairs sWM by decreasing the specificity of neuronal responses to spatial locations through broadened spatial tuning. Testing the relevance of this mechanism in humans remains a vital gap in our understanding of sWM and is critical for designing better treatments for WM impairments.</p><p><strong>Methods: </strong>To overcome the challenges of measuring neuronal responses invasively in humans, we combined pharmacological manipulation and computational fMRI to show that ketamine broadens neural spatial tuning in healthy adults (N=40). Specifically, we modeled population neuron-level representations, rather than traditionally examined changes in blood oxygen level dependent (BOLD) activation.</p><p><strong>Results: </strong>Broader neural tuning across visual perception and WM networks was linked to poorer sWM performance under ketamine, implicating tuning changes in sWM deficits. Furthermore, ketamine-induced changes in tuning, compared to the overall magnitude of BOLD activation, were more consistent across individuals and brain regions, suggesting a collective effect of ketamine on neural tuning across spatially-selective regions.</p><p><strong>Conclusions: </strong>These findings provide the first empirical evidence linking altered neuronal tuning to NMDAR antagonism and sWM impairments in humans, advancing a mechanistic understanding of glutamatergic mechanisms underlying sWM and related deficits in neuropsychiatric disorders.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073196","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":"Women's Brain Health in the Era of Precision Neuroimaging.","authors":"Elle M Murata, Hannah Grotzinger, Magdalena Martínez-García, Carina Heller, Susana Carmona, Sheila Shanmugan, Laura Pritschet, Emily G Jacobs","doi":"10.1016/j.biopsych.2026.09.011","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.011","url":null,"abstract":"<p><p>The mammalian brain is dynamically shaped by endocrine rhythms, yet the field of human neuroscience has historically studied the brain in isolation from these biological signals. This review synthesizes evidence from dense-sampling studies that probe endocrine-nervous system coupling over major steroid hormone transitions, including the menstrual cycle and pregnancy. We highlight ways in which precision imaging may be uniquely equipped to elucidate the neurobiological underpinnings of why hormonal transition periods are major inflection points for the emergence of mood disorders. Dense-sampling designs are also poised to resolve major gaps in our basic understanding of brain-hormone coupling during the onset and cessation of reproductive function. The next era of precision neuroimaging will benefit from integrating dense-sampling approaches over hormonal transitions with personalized functional mapping methods to resolve how hormone rhythms shape individual-specific brain organization, laying the foundation for precise models of women's brain health across the lifespan.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057879","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":"GABAergic interneurons in local circuits of primate prefrontal cortex.","authors":"Stefan Pommer, David A Lewis, Fenna Krienen, Michael Feyerabend, Beatriz Rico, Shreejoy Tripathy, Julio Martinez-Trujillo, Guillermo Gonzalez-Burgos, Andreas Neef, Jochen F Staiger","doi":"10.1016/j.biopsych.2026.09.012","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.012","url":null,"abstract":"<p><p>Cortical GABAergic interneurons exhibit remarkable diversity of morphological, electrophysiological and molecular features, which underlies their specialized roles in circuit functions. Molecular characteristics have proven to be a reasonable starting point in the past for classification, grouping them into parvalbumin (PV), somatostatin (SST), vasoactive intestinal polypeptide (VIP) and \"others\" (e.g. LAMP5). While Patch-seq studies provide valuable insight into human cortical interneurons, similar results from non-human primates are lagging behind. This is problematic because the studying of cell types, circuits and behavior in a detailed experimental fashion is still out of reach in the human. Therefore, using the extensive knowledge from the mouse model as a ground truth, we explore how recent studies of GABAergic interneurons in marmoset and macaque add to our understanding of the expanding variety of cell types and subtypes in primates compared to rodents. Our knowledge of which interneuron participates in which basic circuit motif, like feedforward, feedback, local and lateral inhibition as well as disinhibition is still very limited. However, the more diverse molecular, physiological and morphological features of primate interneurons should allow a broader range of circuit motifs, increasing the computational power of prefrontal cortical circuits. This increased complexity likely supports advanced cognitive functions such as working memory but may also heighten vulnerability to neuropsychiatric disorders. We argue that primate-specific interneuron diversity is not merely a quantitative expansion but a functional innovation, with profound implications for understanding cognition and disease.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036443","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 physiology of mental representations: from single neurons to circuits.","authors":"Christos Constantinidis, Stefan Everling, Stefan Treue, Raymond Ka Wong, Min Wang, Shengtao Yang, Julio Martinez-Trujillo","doi":"10.1016/j.biopsych.2026.09.009","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.009","url":null,"abstract":"<p><p>Mental representations enable the brain to transcend the immediacy of sensory input and operate on internal models of the world. Working memory (WM) provides the neural substrate that maintains, manipulates, and accesses these representations over behaviorally relevant timescales. Early studies identified persistent neuronal activity in the dorsolateral prefrontal cortex (dlPFC) as a key mechanism supporting WM, arising from specialized recurrent microcircuits in which excitatory and inhibitory interactions sustain information in the absence of external stimulation. Subsequent research has revealed a richer and more diverse set of mechanisms underlying WM representations. Depending on task demands, cognitive state, and behavioral context, information can be encoded through persistent activity, oscillations, activity-silent synaptic processes, and temporally structured neural sequences. These representational formats emerge from canonical cortical microcircuits composed of excitatory and inhibitory neurons whose physiological properties vary across brain regions. Interactions between WM, attention, and executive control ensure that internal representations are selectively maintained, updated, and flexibly deployed to guide reasoning, planning, and decision-making. At a broader systems level, WM representations distributed across prefrontal, association and sensory cortices may occupy low-dimensional neural manifolds whose geometry defines the content of conscious access, allowing memories, goals, and imagined scenarios to enter awareness even in the absence of sensory input. Together, current evidence suggests that WM representations are emergent properties of recurrent, hierarchical neural networks whose dynamics are continuously shaped by context, experience, and behavioral demands, providing a flexible neural architecture for adaptive cognition and conscious thought.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029565","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":"Sex-specific role of systemic inflammation in moderating the association between choroid plexus volume and depressive severity: findings from sBEAD cohort.","authors":"Xiaofang Cheng, Zhuozhi Dai, Jianshan Chen, Xiaofei Zhang, Jiaqi Sun, Ruilan Yang, Amei Chen, Zhuoyong Cheng, Tianhe Pan, Ziyi Song, Qiuxia Wu, Haishan Wu, Xiuling Wu, Yanlong Jia, Yingmei Chen, Daomeng Cheng, Yanling Zhou, Biyu Ye, Xuan Li, Chanjuan Yang, Xinhua Wei, Liping Cao","doi":"10.1016/j.biopsych.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.010","url":null,"abstract":"<p><strong>Background: </strong>Accumulating evidence implicates peripheral inflammation and glymphatic dysfunction in adult major depressive disorder (MDD), but whether glymphatic impairment exists in adolescent MDD and how it interacts with systemic inflammation remains unknown.</p><p><strong>Methods: </strong>Data were derived from the Symptomatic Trajectory and Biomarkers of Early Adolescent MDD (sBEAD) study. The sample comprised 461 adolescents with MDD and 253 healthy controls. Multimodal magnetic resonance imaging-derived markers of glymphatic function, including the diffusion tensor imaging along the perivascular space index, free water fraction, perivascular space volume, and choroid plexus (CP) volume, were investigated, as well as their interaction with peripheral inflammatory and oxidative stress indices.</p><p><strong>Results: </strong>Compared with healthy controls, adolescents with MDD exhibited a significantly elevated diffusion tensor imaging along the perivascular space index, increased free water fraction, and higher systemic immune-inflammation index (SII) levels. Notably, the SII significantly moderated the relationship between CP volume and depression severity: greater CP volume was associated with more severe depression in patients with high SII levels, whereas this association was absent under low SII levels. This moderating effect was significant in female patients, whereas no such effect was detected in males.</p><p><strong>Conclusions: </strong>These findings provide evidence of a synergistic interaction between systemic inflammation and brain clearance pathways in adolescent MDD, highlighting a potential sex-dependent mechanism that may inform targeted interventions for affected subpopulations.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029636","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":"In Vivo Characterization of Fatty Acid Amide Hydrolase in Posttraumatic Stress Disorder: A [¹¹C]CURB Positron Emission Tomography Study.","authors":"Erin V Gaudette, Duncan G J Green, Sarah E Watling, Shahtaj S Dheda, Shamantha J Lora, Maia Zilberman, Matthew N Hill, Rachel F Tyndale, J Don Richardson, Tina McCluskey, Lucas Narciso, Pablo M Rusjan, Stefan Kloiber, Sylvain Houle, Jerry J Warsh, Isabelle Boileau","doi":"10.1016/j.biopsych.2026.09.008","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.09.008","url":null,"abstract":"<p><strong>Background: </strong>Posttraumatic stress disorder (PTSD) is associated with impaired fear extinction and dysfunction in amygdala-centered circuits, for which treatments remain insufficient. The endocannabinoid system, particularly anandamide signaling regulated by fatty acid amide hydrolase (FAAH), has been implicated in stress and fear regulation. Preclinical studies suggest increased FAAH is linked to heightened stress responsivity, but FAAH status in PTSD remains unclear. We used [¹¹C]CURB positron emission tomography (PET) to characterize FAAH levels in the amygdala and in corticolimbic regions in PTSD and examine associations with clinical symptoms.</p><p><strong>Methods: </strong>Participants with PTSD and controls underwent clinical assessment and PET/MRI. Trauma histories were characterized using clinical interviews and the Traumatic Life Events Questionnaire (TLEQ). FAAH levels ([¹¹C]CURB) were quantified using an irreversible two-tissue compartment model with arterial input function. Associations with PTSD symptoms were examined.</p><p><strong>Results: </strong>86 participants were included (35 PTSD, 51 controls). PTSD participants showed lower amygdala FAAH levels than controls (-10%; p = 0.02), with no differences in other corticolimbic regions. Exploratory analyses showed that childhood trauma was associated with higher corticolimbic FAAH levels, irrespective of diagnosis (+11.6%; p = 0.014; n = 28 vs. 24 with TLEQ data). FAAH levels were not associated with clinical symptoms.</p><p><strong>Conclusions: </strong>Despite preclinical evidence linking increased FAAH activity to stress-related phenotypes, we found reduced amygdala FAAH in PTSD. Exploratory analyses showed higher corticolimbic FAAH in individuals with childhood trauma. These findings provide in vivo evidence of altered endocannabinoid signaling in PTSD and may inform interpretation of limited efficacy in FAAH inhibitor trials.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023837","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 cell type-specific switch in GluN2D NMDA receptors drives cortical circuit hyperexcitability and sensory-driven cortical synchronization deficits in a Fragile X Syndrome model.","authors":"Aleya Shedd, Carrie Jonak, Leo Chan, Samantha Assad, Shashank Dravid, Jay Gibson, Devin Binder, Kimberly Huber","doi":"10.1016/j.biopsych.2026.09.007","DOIUrl":"10.1016/j.biopsych.2026.09.007","url":null,"abstract":"<p><strong>Background: </strong>Altered sensory processing and sensitivity are prevalent in Fragile X Syndrome (FXS) and may be mediated by dysfunction of cortical circuits. Evidence from individuals with FXS and/or the FXS mouse model, Fmr1 KO, indicates hyperexcitability of sensory cortical circuits, deficits in sensory-driven circuit synchrony and sensory-induced seizures. GluN2D-containing NMDA receptors (NMDARs) are enriched in cortical inhibitory neurons. We hypothesized that selective activation of GluN2D may correct cortical circuit hyperexcitability, seizures, and synchrony deficits in Fmr1 KO mice.</p><p><strong>Methods: </strong>To test this hypothesis, we used pharmacology and cell type-specific genetic manipulation of GluN2D combined with multi-unit and single cell electrophysiology in cortical slices and multielectrode EEG in vivo to examine the functional contribution of GluN2D to cortical circuit dysfunction in the Fmr1 KO mouse.</p><p><strong>Results: </strong>In contrast to our hypothesis, pharmacological inhibition of GluN2D-containing NMDARs corrects cortical circuit hyperexcitability, reduces sensory-driven seizures and improves EEG synchrony in Fmr1 KO mice. We demonstrate a switch in the cell type-specific functional expression of GluN2D-containing NMDARs in Fmr1 KO, from inhibitory to excitatory cortical neurons, which drives circuit hyperexcitability. In support of this conclusion, the mRNA for GluN2D (Grin2d) is upregulated in Fmr1 KO excitatory neurons and genetic reduction of Grin2d in excitatory neurons corrects measures of circuit hyperexcitability in Fmr1 KO mice.</p><p><strong>Conclusions: </strong>Our results reveal an unexpected cell type-specific switch in GluN2D-containing NMDARs in a model of a major genetic cause of intellectual disability and autism and suggest a novel therapeutic strategy to aid sensory processing deficits in FXS.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015583","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}