Translational Psychiatry最新文献

{"title":"The disappointment centre of the brain gets exciting: a systematic review of habenula dysfunction in depression.","authors":"Sarah Cameron, Katrina Weston-Green, Kelly A Newell","doi":"10.1038/s41398-024-03199-x","DOIUrl":"10.1038/s41398-024-03199-x","url":null,"abstract":"<p><strong>Background: </strong>The habenula is an epithalamic brain structure that acts as a neuroanatomical hub connecting the limbic forebrain to the major monoamine centres. Abnormal habenula activity is increasingly implicated in depression, with a surge in publications on this topic in the last 5 years. Direct activation of the habenula is sufficient to induce a depressive phenotype in rodents, suggesting a causative role in depression. However, the molecular basis of habenula dysfunction in depression remains elusive and it is unclear how the preclinical advancements translate to the clinical field.</p><p><strong>Methods: </strong>A systematic literature search was conducted following the PRISMA guidelines. The two search terms depress* and habenula* were applied across Scopus, Web of Science and PubMed databases. Studies eligible for inclusion must have examined the habenula in clinical cases of depression or preclinical models of depression and compared their measures to an appropriate control.</p><p><strong>Results: </strong>Preclinical studies (n = 63) measured markers of habenula activity (n = 16) and neuronal firing (n = 22), largely implicating habenula hyperactivity in depression. Neurotransmission was briefly explored (n = 15), suggesting imbalances within excitatory and inhibitory habenula signalling. Additional preclinical studies reported neuroconnectivity (n = 1), inflammatory (n = 3), genomic (n = 3) and circadian rhythm (n = 3) abnormalities. Seven preclinical studies (11%) included both males and females. From these, 5 studies (71%) reported a significant difference between the sexes in at least one habenula measure taken. Clinical studies (n = 24) reported abnormalities in habenula connectivity (n = 15), volume (n = 6) and molecular markers (n = 3). Clinical studies generally included male and female subjects (n = 16), however, few of these studies examined sex as a biological variable (n = 6).</p><p><strong>Conclusions: </strong>Both preclinical and clinical evidence suggest the habenula is disrupted in depression. However, there are opportunities for sex-specific analyses across both areas. Preclinical evidence consistently suggests habenula hyperactivity as a primary driver for the development of depressive symptoms. Clinical studies support gross habenula abnormalities such as altered activation, connectivity, and volume, with emerging evidence of blood brain barrier dysfunction, however, progress is limited by a lack of detailed molecular analyses and limited imaging resolution.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"499"},"PeriodicalIF":5.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11659325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations of the endocannabinoid system in adolescents with non-suicidal self-injury as a function of childhood maltreatment.","authors":"Marc D Ferger, Christine Sigrist, Susanne Brodesser, Michael Kaess, Julian Koenig","doi":"10.1038/s41398-024-03205-2","DOIUrl":"10.1038/s41398-024-03205-2","url":null,"abstract":"<p><p>Non-suicidal self-injury (NSSI) is a highly prevalent phenomenon in adolescence, often associated with prior traumatic experiences. The development and maintenance of NSSI is associated with dysregulation of the stress response, and evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis plays an important role. The endocannabinoid system is a neuromodulatory system in close functional interaction with the HPA axis. Several studies have reported alterations of the endocannabinoid system in adult patients with post-traumatic stress disorder. However, the role of the endocannabinoid system in children and adolescents with NSSI is less clear, and previously no study examined endocannabinoids in youth with experiences of maltreatment. N-arachidonyl ethanolamide (AEA) and 2-arachidonyl glycerol (2-AG) were quantified alongside sociodemographic and clinical characteristics in n = 148 adolescents (12-17 years of age). Analyses addressed group differences comparing healthy controls (HC, n = 38), patients with NSSI without (NSSI - CMT, n = 42) and with a history of childhood maltreatment (NSSI + CMT, n = 68). We show that AEA is reduced in adolescents with NSSI independent of childhood maltreatment. Further, we present first evidence for a negative association between AEA and NSSI frequency as well as AEA and the severity of childhood maltreatment. This is the first study providing evidence for alterations in the endocannabinoid system in children and adolescents engaging in repetitive NSSI. Findings from the study support current endocannabinoid-hypotheses on the neurobiology of trauma and adversity, extending existing findings of altered endocannabinoid signaling following exposure to traumatic events to a well-powered sample of children and adolescents.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"491"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinically relevant MEK inhibitor mirdametinib combined with D-cycloserine and prediction error disrupts fear memory in PTSD models.","authors":"Sanket B Raut, Fanny Joly, Nikolas K Haass, Rajaraman Eri, Juan J Canales, David M Benedek, Robert J Ursano, Luke R Johnson","doi":"10.1038/s41398-024-03190-6","DOIUrl":"10.1038/s41398-024-03190-6","url":null,"abstract":"<p><p>This study establishes mirdametinib as the first MEK inhibitor that can undergo clinical development for psychiatric indications such as post-traumatic stress disorder (PTSD). PTSD is characterized by persistent traumatic memories with limited effective treatment options. A body of evidence suggests that memory storage is dynamic and constantly updated through post-retrieval modification a process termed reconsolidation. Although ERK/MAPK signaling plays a central role in fear memory consolidation, no clinically translatable MEK inhibitor has been tested in experimental models or in clinical trials to disrupt this process. Furthermore, there is need to develop pharmacological and behavioral strategies to labilize the memory to make it susceptible for disruption. Here, we disrupted fear memory reconsolidation with the clinically relevant MEK inhibitor mirdametinib in C57BL/6 mice and tested memory destabilization strategies using an auditory fear conditioning paradigm, with drugs administered following reactivation of memory. We found prediction error effective in labilizing weak fear memory and combined D-cycloserine (DCS) and predication error effective in labilizing strong fear memory. Mirdametinib disrupted the weak fear memory and reduced ERK phosphorylation in lateral amygdala when coupled with prediction error at the time of memory reactivation but required coordinated combination of DCS, prediction error and mirdametinib to disrupt strong fear memory. Barnes maze spatial memory test and open field test revealed that mirdametinib did not affect retrieval of other forms (spatial) of long-term memory and locomotor activity. Furthermore, the effect of mirdametinib was specific to reconsolidation as it had no effect on fear memory when given without reactivation. These translational findings identify a new drug that can be adapted for the treatment of PTSD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"492"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of gut microbiota and metabolomic pathways in modulating the efficacy of SSRIs for major depressive disorder.","authors":"Ying Jiang, Yucai Qu, Lingyi Shi, Mengmeng Ou, Zhiqiang Du, Zhenhe Zhou, Hongliang Zhou, Haohao Zhu","doi":"10.1038/s41398-024-03208-z","DOIUrl":"10.1038/s41398-024-03208-z","url":null,"abstract":"<p><p>This study aims to explore the mechanism by which gut microbiota influences the antidepressant effects of serotonin reuptake inhibitors (SSRIs) through metabolic pathways. A total of 126 patients were analyzed for their gut microbiota and metabolomics. Patients received SSRI treatment and were categorized into responder and non-responder groups based on changes in their Hamilton Depression Rating Scale (HAMD-17) scores before and after treatment. The association between gut microbiota composition and the efficacy of SSRIs was investigated through 16S rRNA gene sequencing and metabolomic analysis, and a predictive model was developed. As a result, the study found significant differences in gut microbiota composition between the responder and resistant groups. Specific taxa, such as Ruminococcus, Bifidobacterium, and Faecalibacterium, were more abundant in the responder group. Functional analysis revealed upregulation of acetate degradation and neurotransmitter synthesis pathways in the responder group. The machine learning model indicated that gut microbiota and metabolites are potential biomarkers for predicting SSRIs efficacy. In conclusion, gut microbiota influences the antidepressant effects of SSRIs through metabolic pathways. The diversity and function of gut microbiota can serve as biomarkers for predicting the treatment response, providing new insights for personalized treatment.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"493"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of the gut microbiota-inflammation-brain axis in unmedicated bipolar disorder II depression.","authors":"Zixuan Guo, Shu Xiao, Guanmao Chen, Shuming Zhong, Hui Zhong, Shilin Sun, Pan Chen, Xinyue Tang, Hengwen Yang, Yanbin Jia, Zhinan Yin, Li Huang, Ying Wang","doi":"10.1038/s41398-024-03207-0","DOIUrl":"10.1038/s41398-024-03207-0","url":null,"abstract":"<p><p>The relationships of the gut microbiota-inflammation-brain axis in depressive bipolar disorder (BD) remains under-elaborated. Sixty-five unmedicated depressive patients with BD II and 58 controls (HCs) were prospectively enrolled. Resting-state functional MRI data of static and dynamic amplitude of low-frequency fluctuation (ALFF) was measured, and abnormal ALFF masks were subsequently set as regions of interest to calculate whole-brain static functional connectivity (sFC) and dynamic functional connectivity (dFC). Fecal samples were collected to assess gut diversity and enterotypes using 16S amplicon sequencing. Blood samples were also collected, serum was assayed for levels of cytokines (interleukin [IL]-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor [TNF]-α). Patients with BD II exhibited decreased static ALFF values in the left cerebellum Crus II, and decreased cerebellar sFC and dFC to the right inferior parietal lobule and right superior frontal gyrus, respectively. Moreover, higher pro-inflammatory and anti-inflammatory cytokines levels, and increased proinflammatory bacteria and glutamate and gamma-aminobutyric acid metabolism related bacteria were identified in BD II. The interaction of Parabacteroides levels × IL-8 levels was an independent contributor to static ALFF in the left cerebellar Crus II. The findings bridged a gap in the underlying pathophysiological mechanism of the gut microbiota-inflammation-brain axis in BD II depression.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"495"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking ambient air pollution to mental health: evidence based on the two-sample Mendelian randomization and colocalization study.","authors":"Huanhuan Fan, Junhong Li, Yikai Dou, Yushun Yan, Min Wang, Xiao Yang, Xiaohong Ma","doi":"10.1038/s41398-024-03196-0","DOIUrl":"10.1038/s41398-024-03196-0","url":null,"abstract":"<p><p>Growing evidence links air pollution, a ubiquitous environmental stressor, to a higher risk of developing mental disorders, raising significant public health concerns. Mental disorders represent a significant global public health challenge which can have a profound impact on individual lives. In this study, we used Mendelian randomization (MR) to investigate the causal relationship between ambient air pollution and four common mental disorders. Genome-wide association study (GWAS) data for ambient air pollution and summary-level GWAS data for four representative mental disorders were obtained from open-access database. Inverse variance weighted (IVW) method with multiplicative random-effects model was the main analysis. Sensitivity analyses were conducted to validate the results. Bayesian colocalization analysis was conducted to explore the potential shared genetic causal variants between specific air pollutants and mental disorders. A suggestive association was observed between political matter (PM) 2.5 and anxiety disorders (OR 2.96, 95%CI 1.29-6.81, p = 0.010). Exposure to nitrogen dioxide (NO2) was significantly linked to an elevated risk of schizophrenia (OR 1.95, 95% CI 1.45-2.63, p = 1.13E-05) and showed a nominal association with an increased risk of bipolar disorder (OR 1.43, 95% CI 1.09-1.86, p = 0.009). A suggestive causal association was detected between nitrogen oxides (NOx) and anxiety disorder (OR 2.90, 95%CI 1.21-6.97, p = 0.017). No significant association was detected between exposure to PM2.5-10, PM10 and mental disorders. No significant horizonal pleiotropy and heterogeneity was found. The colocalization analysis revealed robust evidence supporting the colocalization of NO2 with schizophrenia at SNP rs12203592. Our findings support causal associations between exposure to ambient air pollution, particularly PM2.5, NO₂, and NOx, and an increased risk of specific mental disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"489"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia.","authors":"Zhixin Bai, Peilong Li, Xu Gao, Gaoyu Zu, Andrew Jiang, Keting Wu, Naguib Mechawar, Gustavo Turecki, Klaus Lehnert, Russell G Snell, Jin Zhou, Jia Hu, Bingbing Yan, Liang Chen, Wensheng Li, You Chen, Shuai Liu, Ying Zhu, Linya You","doi":"10.1038/s41398-024-03202-5","DOIUrl":"10.1038/s41398-024-03202-5","url":null,"abstract":"<p><p>Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase. Gene co-expression analysis (WGCNA) showed a strong correlation of caudate MSNs and gene module green, with a PDE5A-containing hub gene network. Gene regulatory network analysis (SCENIC) indicated key regulons among different cell types and basal ganglia regions, with downstream targets of key transcriptional factors showing overlapping genes such as PDEs. Upregulation of PDE5A was further validated in 7 pairs of control and BD caudate sections. Overexpression of PDE5A in primary cultured lateral ganglion eminence-derived striatal neurons led to decreased dendrite complexity, increased apoptosis, and enhanced neuronal excitability and membrane resistance. This effect could be rescued by PDE5 specific inhibitor, tadalafil. Overexpression of PDE5A in mouse striatum by stereotaxic injection caused a decreased cGMP level, an increased gene expression profile of neuroinflammation, and BD-like behaviors. Collectively, our findings provided cell type-specific gene expression profile, and indicated a causative role of PDE5A upregulation in BD basal ganglia. This study provides a single-nucleus transcriptomic profile of human control and bipolar disorder (BD) basal ganglia. Differential expression, gene co-expression, and gene regulatory network analyses collectively indicated upregulation of PDE5A in BD caudate medium spiny neurons (MSNs), which was further validated in another cohort of BD brains. The causative role of PDE5A upregulation in BD etiology is supported by the effects of PDE5A overexpression in cultured mouse MSNs in vitro and in adult mouse striatum in vivo. The former led to reduced dendrite complexity, increased apoptosis, and neuronal hyper-excitability, which could be rescued by PDE5 specific inhibitor tadalafil. The latter caused lower cGMP levels, upregulated genes associated with neuroinflammation, and BD-like behaviors.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"494"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prefrontal cortex stimulation normalizes deficient adaptive learning from outcome contingencies in low mood.","authors":"Verena Sarrazin, Margot Juliëtte Overman, Luca Mezossy-Dona, Michael Browning, Jacinta O'Shea","doi":"10.1038/s41398-024-03204-3","DOIUrl":"10.1038/s41398-024-03204-3","url":null,"abstract":"<p><p>Depression and anxiety are associated with deficits in adjusting learning behaviour to changing outcome contingencies. This is likely to drive and maintain symptoms, for instance, by perpetuating negative biases or a sense of uncontrollability. Normalising such deficits in adaptive learning might therefore be a novel treatment target for affective disorders. The aim of this experimental medicine study was to test whether prefrontal cortex transcranial direct current stimulation (tDCS) could normalise these aberrant learning processes in depressed mood. To test proof-of-concept, we combined tDCS with a decision-making paradigm that manipulates the volatility of reward and punishment associations. 85 participants with low mood received tDCS during (or before) the task. In two sessions participants received real or sham tDCS in counter-balanced order. Compared to healthy controls (n = 40), individuals with low mood showed significantly impaired adjustment of learning rates to the volatility of loss outcomes. Prefrontal tDCS applied during task performance normalised this deficit, by increasing the adjustment of loss learning rates. As predicted, prefrontal tDCS before task performance (control) had no effect. Thus, the effect was cognitive-state dependent. Our study shows, for the first time, that a candidate depression treatment, prefrontal tDCS, when paired with a task, can reverse deficits in adaptive learning from outcome contingencies in low mood. Thus, combining neurostimulation with a concurrent cognitive manipulation is a potential novel strategy to enhance the effect of tDCS in depression treatment.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"487"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Craving changes in first 14 days of addiction treatment: an outcome predictor of 5 years substance use status?","authors":"Emmanuelle Baillet, Marc Auriacombe, Cassandre Romao, Hélène Garnier, Christophe Gauld, Chloé Vacher, Joël Swendsen, Mélina Fatseas, Fuschia Serre","doi":"10.1038/s41398-024-03193-3","DOIUrl":"10.1038/s41398-024-03193-3","url":null,"abstract":"<p><p>Addiction is considered a chronic disorder that requires long-term treatment. Early identification of predictors of outcome may enable better and early adjustment of treatment. Daily fluctuations of craving have been shown to predict substance use within hours, making it a major target for treatment. The objective of this study was to examine whether trajectory and temporal dynamics of craving, at the initiation of outpatient addiction treatment, were associated to long-term substance use outcome. An Ecological Momentary Assessment study collected craving intensity changes and substance use during the first 14-days of treatment, followed by prospective regular follow-ups for 5 years or more to assess long-term outcome. Analysis investigated whether individual differences in craving trajectory (linear trend) and dynamics (inertia, variability and instability) predicted 5+ years follow-up outcome: substance use (1 day or more of primary substance use/past 30 days) versus abstinence. Thirty-nine participants were enrolled in addiction clinic in Bordeaux, France. Results showed that substance use at 5+ years was significantly associated with slower decrease of craving intensity (p < 0.001), and a lower craving inertia (p = 0.038), i.e. tendency to persist from one moment to the other, compared to abstinence status. Conversely, craving intensity was not found associated with substance use/abstinence at follow-up. Results suggest that a slower decrease in craving at treatment initiation could express a greater resistance to treatment. This resistance may have many mechanisms, among which a persistent reactivity to cues - as suggested by lower inertia - that could constitute a vulnerability to use and a valuable indicator of long-term outcomes.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"497"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABA_AR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation.","authors":"Jia Tong, Jingjing Gao, Yawei Qi, Ziyan Gao, Qianqian Wang, Yang Liu, Tiangang Yuan, Minglong Ren, Guixia Yang, Zhaoyue Li, Jin Li, Hongyuan Sun, Xing Zhao, Yeung-Yeung Leung, Yonghui Mu, Jiamin Xu, Chengbiao Lu, Shiyong Peng, Lihao Ge","doi":"10.1038/s41398-024-03206-1","DOIUrl":"10.1038/s41398-024-03206-1","url":null,"abstract":"<p><p>The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease. In this study, we found that GABA_AR, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1. PPT1 depalmitoylates GABA_AR α1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABA_AR α1 subunit binding site enhanced inhibitory synaptic transmission and strengthened oscillations powers but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1^em1 mice. Our study highlights the critical role of PPT1 in maintaining GABA_AR palmitoylation homeostasis and reveals a previously unknown molecular pathway in CLN1 diseases induced by PPT1 mutations.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"488"},"PeriodicalIF":5.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}