Molecular Psychiatry最新文献

{"title":"Dissociable effects of psilocybin and escitalopram for depression on processing of musical surprises","authors":"Rebecca Harding, Neomi Singer, Matthew B. Wall, Talma Hendler, David Erritzoe, David Nutt, Robin Carhart-Harris, Leor Roseman","doi":"10.1038/s41380-025-03035-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03035-8","url":null,"abstract":"<p>Psilocybin therapy (PT) is emerging as an effective intervention for Major Depressive Disorder (MDD), offering comparable efficacy to conventional treatments like selective serotonin reuptake inhibitors (SSRIs). Music, an emotionally evocative stimulus, provides a valuable tool to explore changes in hedonic and predictive processing mechanisms via expectancy violations, or ‘surprises’. This study sought to compare behavioural and functional magnetic resonance imaging (fMRI) responses to musical surprises in MDD patients treated with either PT or the SSRI, escitalopram. In this secondary analysis of a trial, 41 MDD patients (with usable fMRI data) were randomly assigned to either PT (<i>n</i> = 22) or escitalopram (<i>n</i> = 19) treatment groups. Participants listened to music during fMRI and tracked their emotional experience, both before and after a 6-week intervention. Surprise-related valence and arousal indices were calculated. Musical surprises were entered as regressors for whole-brain and region of interest fMRI analyses. PT caused a greater decrease in anhedonia scores compared with escitalopram. While escitalopram led to reductions in surprise-related affective responses, PT showed no significant change. Escitalopram was associated with increased activation in memory and emotional processing areas during musical surprises (versus control events) when compared with PT. Following PT, there was greater activation in the ventromedial prefrontal cortex and sensory regions, and reduced activation in the angular gyrus. PT may allow for the subjective response to musical surprises to be maintained through a lasting reduction in the salience of prediction errors, or, alternatively, by increasing hedonic priors. Contrastingly, escitalopram may diminish hedonic priors, highlighting fundamental differences in treatment mechanisms.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875998","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":"Genetic approach uncovering the pathways between childhood maltreatment and suicide attempt","authors":"Diyang Qu, Xu Zhang, Yuhao He, Chang Lei, Yuanxia Han, Junkang Lin, Tongtong Cai, Xueping Zhu, Yize Mao, Runsen Chen","doi":"10.1038/s41380-025-02966-6","DOIUrl":"https://doi.org/10.1038/s41380-025-02966-6","url":null,"abstract":"<p>Childhood maltreatment significantly heightens the risk of suicide attempt, but the causal mechanisms and underlying pathways are not fully understood. Using genetic instruments for both childhood maltreatment (<i>n</i> = 185,414) and suicide attempt (cases = 29,782; controls = 519,961), we performed two-sample Mendelian randomization analyses. Our results show that higher level of childhood maltreatment is causally associated with an increased risk of suicide attempt (OR = 3.40; 95% CI, 2.34–4.96, <i>P</i> = 1.3e–10). We then conducted a two-step Mendelian randomization mediation analysis, identifying 11 out of 58 potential mediators between childhood maltreatment and suicide attempt. These mediators included neurobiological, psychopathological and behavioral factors. The psychopathological factors had the most significant impact, accounting for 10.4–50.2% the mediation. This study confirms the causal relationship between childhood maltreatment and suicide attempt, highlighting specific mediators-especially within the psychopathological dimension-that can guide targeted interventions to alleviate the adverse effects of childhood maltreatment and prevent suicide attempt.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"33 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876006","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":"Immunological drivers and potential novel drug targets for major psychiatric, neurodevelopmental, and neurodegenerative conditions","authors":"Christina Dardani, Jamie W. Robinson, Hannah J. Jones, Dheeraj Rai, Evie Stergiakouli, Jakob Grove, Renee Gardner, Andrew M. McIntosh, Alexandra Havdahl, Gibran Hemani, George Davey Smith, Tom G. Richardson, Tom R. Gaunt, Golam M. Khandaker","doi":"10.1038/s41380-025-03032-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03032-x","url":null,"abstract":"<p>Immune dysfunction is implicated in the aetiology of psychiatric, neurodevelopmental, and neurodegenerative conditions, but the issue of causality remains unclear impeding attempts to develop new interventions. Using genomic data on protein and gene expression across blood and brain, we assessed evidence of a potential causal role for 736 immune response-related biomarkers on 7 neuropsychiatric conditions by applying Mendelian randomization (MR) and genetic colocalisation analyses. A systematic three-tier approach, grouping biomarkers based on increasingly stringent criteria, was used to appraise evidence of causality (passing MR sensitivity analyses, colocalisation, False Discovery Rate and Bonferroni thresholds). We provide evidence for a potential causal role of 29 biomarkers for 7 conditions. The identified biomarkers suggest a role of both brain specific and systemic immune response in the aetiology of schizophrenia, Alzheimer’s disease, depression, and bipolar disorder. Of the identified biomarkers, 20 are therapeutically tractable, including <i>ACE</i>, <i>TNFRSF17</i>, <i>SERPING1</i>, <i>AGER</i> and <i>CD40</i>, with drugs currently approved or in advanced clinical trials. Based on the largest available selection of plasma immune-response related biomarkers, our study provides insight into possible influential biomarkers for the aetiology of neuropsychiatric conditions. These genetically prioritised biomarkers now require examination to further evaluate causality, their role in the aetiological mechanisms underlying the conditions, and therapeutic potential.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875999","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 markers of disease risk and psychotherapy response in anxiety disorders – a longitudinal analysis of the DNA methylome","authors":"Katharina Domschke, Miriam A. Schiele, Óscar Crespo Salvador, Lea Zillich, Jan Lipovsek, Andre Pittig, Ingmar Heinig, Isabelle C. Ridderbusch, Benjamin Straube, Jan Richter, Maike Hollandt, Jens Plag, Thomas Fydrich, Katja Koelkebeck, Heike Weber, Ulrike Lueken, Udo Dannlowski, Jürgen Margraf, Silvia Schneider, Elisabeth B. Binder, Andreas Ströhle, Winfried Rief, Tilo Kircher, Paul Pauli, Alfons Hamm, Volker Arolt, Jürgen Hoyer, Hans-Ulrich Wittchen, Angelika Erhardt-Lehmann, Anna Köttgen, Pascal Schlosser, Jürgen Deckert","doi":"10.1038/s41380-025-03038-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03038-5","url":null,"abstract":"<p>Epigenetic mechanisms such as DNA methylation are hypothesized to play a pivotal role in the pathogenesis of anxiety disorders and to predict as well as relate to treatment response. An epigenome-wide association study (EWAS) (Illumina MethylationEPIC BeadChip) was performed at baseline (BL), post-treatment (POST) and 6-month follow-up (FU) in the so far largest longitudinal sample of patients with anxiety disorders (<i>N</i> = 415) treated with exposure-based cognitive behavioral therapy (CBT), and in 315 healthy controls. Independent of comorbidity with depression, anxiety disorders were significantly (<i>p</i> ≤ 6.409E–08) associated with altered DNA methylation at 148 CpGs partly mapping to genes previously implicated in processes related to anxiety, brain disorders, learning or plasticity (e.g., <i>GABBR2</i>, <i>GABRD</i>, <i>GAST</i>, <i>IL12RB2</i>, <i>LINC00293</i>, <i>LOC101928626</i>, <i>MFGE8</i>, <i>NOTCH4</i>, <i>PTPRN2</i>, <i>RIMBP2</i>, <i>SPTBN1</i>) or in a recent cross-anxiety disorders EWAS (<i>TAOK1</i>) after pre-processing and quality control (<i>N</i> = 378 vs. <i>N</i> = 295). Furthermore, BL DNA methylation at seven and three CpGs, respectively, was suggestively (<i>p</i> &lt; 1E–5) associated with treatment response at POST (<i>ABCA7</i>, <i>ADRA2C</i>, <i>LTBR</i>, <i>RPSAP52</i>, <i>SH3RF3</i>, <i>SLC47A2</i>, <i>ZNF251</i>) and FU (<i>ADGRD1</i>, <i>PRSS58</i>, <i>USP47</i>). Finally, suggestive evidence for dynamic epigenome-wide DNA methylation changes along with CBT response emerged at four CpGs from BL to FU (<i>ADIPOR2</i>, <i>EIF3B</i>, <i>OCA2</i>, <i>TMCC1</i>). The identification of epigenetic biomarkers may eventually aid in developing environment-based preventive strategies aimed at increasing resilience by providing deeper molecular insights into the mechanisms underlying anxiety disorders. Defining epigenetic signatures as predictors or key mechanisms in exposure-based interventions could pave the way for more targeted and personalized treatments for anxiety disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"78 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876003","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":"Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial","authors":"Bryan R. Barksdale, Lauren Enten, Annamarie DeMarco, Rachel Kline, Manoj K. Doss, Charles B. Nemeroff, Gregory A. Fonzo","doi":"10.1038/s41380-025-03033-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03033-w","url":null,"abstract":"<p>Mood, anxiety, and trauma-related disorders (MATRDs) are highly prevalent and comorbid. A sizable number of patients do not respond to first-line treatments. Non-invasive neuromodulation is a second-line treatment approach, but current methods rely on cortical targets to indirectly modulate subcortical structures, e.g., the amygdala, implicated in MATRDs. Low-intensity transcranial focused ultrasound (tFUS) is a non-invasive technique for direct subcortical neuromodulation, but its safety, feasibility, and promise as a potential treatment is largely unknown. In a target engagement study, magnetic resonance imaging (MRI)-guided tFUS to the left amygdala was administered during functional MRI (tFUS/fMRI) to test for acute modulation of blood oxygenation level dependent (BOLD) signal in a double-blind, within-subject, sham-controlled design in patients with MATRDs (N = 29) and healthy comparison subjects (N = 23). In an unblinded treatment trial, the same patients then underwent 3-week daily (15 sessions) MRI-guided repetitive tFUS (rtFUS) to the left amygdala to examine safety, feasibility, symptom change, and change in amygdala reactivity to emotional faces. Active vs. sham tFUS/fMRI reduced, on average, left amygdala BOLD signal and produced patient-related differences in hippocampal and insular responses. rtFUS was well-tolerated with no serious adverse events. There were significant reductions on the primary outcome (Mood and Anxiety Symptom Questionnaire General Distress subscale; <i>p</i> = 0.001, Cohen’s <i>d</i> = 0.77), secondary outcomes (Cohen’s <i>d of</i> 0.43–1.50), and amygdala activation to emotional stimuli. Findings provide initial evidence of tFUS capability to modulate amygdala function, rtFUS safety and feasibility in MATRDs, and motivate double-blind randomized controlled trials to examine efficacy.</p><p>ClinicalTrials.gov registration: NCT05228964</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"2 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872686","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":"Estradiol, via estrogen receptor β signaling, mediates stress-susceptibility in the male brain","authors":"Polymnia Georgiou, Abagail F. Postle, Ta-Chung M. Mou, Liam E. Potter, Xiaoxian An, Panos Zanos, Michael S. Patton, Katherine J. Pultorak, Sarah M. Clark, Vien Ngyuyen, Chris F. Powels, Katalin Prokai-Tatrai, Antonis Kirmizis, Istvan Merchenthaler, Laszlo Prokai, Margaret M. McCarthy, Brian N. Mathur, Todd D. Gould","doi":"10.1038/s41380-025-03027-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03027-8","url":null,"abstract":"<p>Dysregulation of normal reward processing via psychological stress contributes to the development of psychiatric disorders. Estrogen is involved in reward processing in females, but this effect has not been well studied in males despite the abundant conversion of androgens to estrogens in the male brain. Here, we used a combination of genetic deletions, behavioral assays, pharmacology, circuit dissection, electrophysiology, in vivo fiber photometry, and optogenetics/chemogenetics to determine the role of the most prevalent and potent estrogen, 17β-estradiol, in male stress-induced reward processing dysfunction. We found that absence of estrogen receptor (ER) β renders male but not female mice susceptible to stress-induced maladaptive reward-processing behaviors. We demonstrated that activation of ERβ-projecting neurons from the basolateral amygdala to nucleus accumbens induced rewarding effects in male, but not female mice. Moreover, we show that the activity of ERβ-expressing neurons projecting from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal male mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive reward processing behaviors and inhibition induces stress susceptibility. We identified that absence of estradiol, but not testosterone per se, underlies susceptibility to stress-mediated dysfunction of rewarding behaviors and that brain-selective delivery of estradiol and intra-basolateral amygdala administration of an ERβ-specific agonist prevent maladaptive reward-processing behaviors in hypogonadal male mice. These findings delineate an estrogen-based mechanism underlying stress susceptibility and provide a novel therapeutic strategy for the treatment of reward-related disorders associated with hypogonadal conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"70 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866708","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":"Reflections on “mitochondrial DNA abundance in blood is associated with Alzheimer’s disease- and dementia-risk”","authors":"Huan Wang, Tianyi Ning, Ziyin Cui, Zedong Cheng","doi":"10.1038/s41380-025-02958-6","DOIUrl":"https://doi.org/10.1038/s41380-025-02958-6","url":null,"abstract":"<p><b>TO THE EDITOR:</b></p><p>We read with great interest the research article titled “Mitochondrial DNA abundance in blood is associated with Alzheimer’s disease- and dementia-risk” [1]. The article by Hannah Stocker et al. offers a significant contribution to the field of dementia research by investigating the association between mitochondrial DNA copy number (mtDNAcn) and the risk of developing Alzheimer’s disease (AD) and other forms of dementia. The study leverages the extensive data from the ESTHER cohort, a large-scale, population-based study in Germany, which followed nearly 10,000 participants over 17 years. This long-term perspective and the comprehensive data collection are major strengths, providing a robust foundation for analyzing the complex relationship between mtDNAcn and dementia risk.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"7 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872685","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":"Subcellular functions of tau mediate repair response and synaptic homeostasis in injury","authors":"Riya Thomas, Die Zhang, Christopher A. Cronkite, Rintu Thomas, Sanjay K. Singh, Lawrence F. Bronk, Rodrigo F. Morales, Joseph G. Duman, David R. Grosshans","doi":"10.1038/s41380-025-03029-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03029-6","url":null,"abstract":"<p>Injury responses in terminally differentiated cells such as neurons are tightly regulated by pathways aiding homeostatic maintenance. Cancer patients subjected to neuronal injury in brain radiation experience cognitive declines similar to those seen in primary neurodegenerative diseases. Numerous studies have investigated the effect of radiation in proliferating cells of the brain, yet the impact in differentiated, post-mitotic neurons, especially the structural and functional alterations remain largely elusive. We identified that microtubule-associated tau is a critical player in neuronal injury response via compartmentalized functions in both repair-centric and synaptic regulatory pathways. Ionizing radiation-induced injury acutely induces an increase in phosphorylated tau in the nucleus where it directly interacts with histone 2AX (H2AX), a DNA damage repair (DDR) marker. Loss of tau significantly reduced H2AX phosphorylation after irradiation, indicating that tau may play an important role in the neuronal DDR response. We also observed that loss of tau increases eukaryotic elongation factor levels, a positive regulator of protein translation after irradiation. This initial response cascades into a significant increase in synaptic proteins, resulting in disrupted homeostasis. Downstream, the novel object recognition test showed a decrease in learning and memory in tau-knockout mice after irradiation, and electroencephalographic activity contained increased delta and theta band oscillations, often seen in dementia patients. Our findings demonstrate tau’s previously undefined, multifunctional role in acute responses to injury, ranging from DDR response in the nucleus to synaptic function within neurons. Such knowledge is vital to develop therapeutic strategies targeting neuronal injury in cognitive decline for at risk and vulnerable populations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"21 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862943","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":"Integrative analysis of miRNA expression profiles reveals distinct and common molecular mechanisms underlying broad diagnostic groups of severe mental disorders","authors":"Pierre Solomon, Lalit Kaurani, Monika Budde, Jean-Baptiste Guiné, Dennis Manfred Krüger, Kevin Riquin, Tonatiuh Pena, Susanne Burkhardt, Cynthia Fourgeux, Kristina Adorjan, Maria Heilbronner, Janos L. Kalman, Mojtaba Oraki Kohshour, Sergi Papiol, Daniela Reich-Erkelenz, Sabrina K. Schaupp, Eva C. Schulte, Fanny Senner, Thomas Vogl, Ion-George Anghelescu, Volker Arolt, Bernhardt T. Baune, Udo Dannlowski, Detlef E. Dietrich, Andreas J. Fallgatter, Christian Figge, Georg Juckel, Carsten Konrad, Jens Reimer, Eva Z. Reininghaus, Max Schmauß, Carsten Spitzer, Jens Wiltfang, Jörg Zimmermann, Anna-Lena Schütz, Farahnaz Sananbenesi, Anne Sauvaget, Peter Falkai, Thomas G. Schulze, André Fischer, Urs Heilbronner, Jeremie Poschmann","doi":"10.1038/s41380-025-03018-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03018-9","url":null,"abstract":"<p>Micro RNAs (miRNAs) play a crucial role as regulators of various biological processes and have been implicated in the pathogenesis of mental disorders such as schizophrenia and bipolar disorders. In this study, we investigate the expression patterns of miRNAs in the PsyCourse Study (<i>n</i> = 1786), contrasting three broad diagnostic groups: Psychotic (Schizophrenia-spectrum disorders), Affective (Bipolar Disorder I, II and recurrent Depression), and neurotypic healthy individuals. Through comprehensive analyses, including differential miRNA expression, miRNA transcriptome-wide association study (TWAS), and predictive modelling, we identified multiple miRNAs unique to Psychotic and Affective groups as well as shared by both. Furthermore, we performed integrative analysis to identify the target genes of the dysregulated miRNAs and elucidate their potential roles in psychosis. Our findings reveal significant alterations of multiple miRNAs such as miR-584-3p and miR-99b-5p across the studied diagnostic groups, highlighting their role as molecular correlates. Additionally, the miRNA TWAS analysis discovered previously known and novel genetically dysregulated miRNAs confirming the relevance in the etiology of the diagnostic groups. Importantly, novel factors and putative molecular mechanisms underlying these groups were uncovered through the integration of miRNA-target gene interactions. This comprehensive investigation provides valuable insights into the molecular underpinnings of severe mental disorders, shedding light on the complex regulatory networks involving miRNAs.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"26 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863001","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":"LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons","authors":"Chuyu Chen, Meghan Masotti, Nathaniel Shepard, Vanessa Promes, Giulia Tombesi, Daniel Arango, Claudia Manzoni, Elisa Greggio, Sabine Hilfiker, Yevgenia Kozorovitskiy, Loukia Parisiadou","doi":"10.1038/s41380-025-03030-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03030-z","url":null,"abstract":"<p>Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson’s disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson’s disease-associated leucine-rich repeat kinase 2 (LRRK2) has an essential role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor side effects of haloperidol. This work opens up new therapeutic avenues for dopamine-related disorders, such as psychosis, also furthering our understanding of Parkinson’s disease pathophysiology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866709","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}