Neurobiology of Disease最新文献

{"title":"Tissue-specific immune and MAPK signatures in models of reduced Progranulin and Western diet","authors":"Andrea R. Merchak ,&nbsp;Maria Elizabeth de Sousa Rodrigues ,&nbsp;Cassandra Cole ,&nbsp;Noelle Neighbarger ,&nbsp;Nilay Bhavsar ,&nbsp;Rebecca L. Wallings ,&nbsp;Valerie Joers ,&nbsp;Jianjun Chang ,&nbsp;Sean D. Kelly ,&nbsp;Timothy R. Sampson ,&nbsp;Malú Gámez Tansey","doi":"10.1016/j.nbd.2026.107287","DOIUrl":"10.1016/j.nbd.2026.107287","url":null,"abstract":"<div><div>Neurodegenerative disorders such as frontotemporal dementia (FTD) have strong hereditary links, yet these genes do not have full penetrance and environmental influences determine the lifetime risk of disease development. Better understanding of the environmental risk factors that determine age of onset, progression, and severity is needed. How these risk factors interact with genetic predisposition for these disorders will allow clinicians to provide better lifestyle recommendations for people with a familial history and deliver more personalized medicine. Here we examine the dose-dependent effects of the gene encoding progranulin (<em>Grn</em>), one of the most common mutations associated with familial FTD. We utilize both homozygous loss and heterozygous knockdown of <em>Grn</em> with the objective of assessing how a western diet consisting of high-fat and high-carbohydrate intake modulates the inflammatory and metabolic hallmarks in middle-aged mice. We found that while full <em>Grn</em> loss leads to heighted antigen presentation machinery and immune cell infiltration in the brain after obesogenic diet, a heterozygous gene primarily affects the periphery. Yet, further examination by RNA sequencing reveals that heterozygous mice have a disruption of MAPK signaling in the brain highlighting early disruption in the neuronal landscape. Our findings are consistent with reports that in individuals with genetic predisposition for FTD due to a <em>GRN</em> mutation, a western-style diet exacerbates the cellular stress in the peripheral immune system and affects the function of the prefrontal cortex. These data further support the use of heterozygous <em>Grn</em> knockout mice as a model for prodromal FTD in addition to the more common <em>Grn</em> full knockout which may not as accurately reflect disease onset biology.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107287"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to ‘Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor’ [Neurobiology of Disease Volume 124 April 2019 Pages 489–504]","authors":"Daniel Ryskamp ,&nbsp;Lili Wu ,&nbsp;Jun Wu ,&nbsp;Dabin Kim ,&nbsp;Gerhard Rammes ,&nbsp;Michal Geva ,&nbsp;Michael Hayden ,&nbsp;Ilya Bezprozvanny","doi":"10.1016/j.nbd.2026.107311","DOIUrl":"10.1016/j.nbd.2026.107311","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107311"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A neuropeptide receptor–enriched transcriptional state characterizes resilient dopaminergic neurons in Parkinson's disease","authors":"Qimeng Zheng ,&nbsp;Xiaoke Lin ,&nbsp;Guoqiang Fei ,&nbsp;Lei Xiao","doi":"10.1016/j.nbd.2026.107303","DOIUrl":"10.1016/j.nbd.2026.107303","url":null,"abstract":"<div><div>Dopaminergic neurons (DANs) exhibit subtype-specific vulnerability in Parkinson's disease (PD), but the molecular basis of selective resilience remains poorly understood. Here, we investigated the role of neuropeptide receptor (NPR) signaling in DAN survival using single-nucleus RNA sequencing of 8065 DANs from postmortem substantia nigra of individuals with PD and matched controls. Despite pronounced neuronal loss in PD, surviving DANs showed a higher NPR transcript burden and increased NPR gene co-expression per cell. Using a 25-gene NPR score, we stratified DANs into high-, mid-, and low-NPR tiers and identified distinct molecular signatures. High-NPR DANs exhibited increased expression of the resilience marker <em>CALB1</em> and an inverse correlation with PD genetic-risk signals. Low-NPR DANs preferentially expressed vulnerability markers (<em>SOX6</em>, <em>ALDH1A1</em>, <em>AGTR1</em>) and displayed a positive association with PD genetic risk. Notably, Mitochondrial Complex I subunits (<em>NDUFS2</em>, <em>NDUFB10</em>) were relatively enriched in low-NPR DANs at baseline and were further reduced in PD specifically within this tier. Among dopaminergic subtypes, the PD-susceptible SOX6_AGTR1 neurons displayed minimal NPR activity, while resilient <em>CALB1</em>⁺ subtypes showed elevated NPR signaling. Moreover, SOX6_AGTR1 neurons preferentially expressed the transcription factors <em>PGR</em> and <em>CLOCK</em>, but the expression of both factors was significantly reduced in PD within this subtype, with no significant change in <em>CALB1</em>⁺ subtypes. Integrating these findings with genome-wide association study (GWAS) enrichment and external datasets, we identified <em>PRLR</em> and <em>CRHR1</em> as key mediators of dopaminergic resilience, highlighting their potential as targets for neuroprotective therapy. Together, our data implicate NPR signaling as a molecular correlate of dopaminergic resilience in PD and highlight specific receptor pathways for therapeutic development.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107303"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resilience and susceptibility to fear extinction are associated with alterations in neurogenesis and brain-wide activity","authors":"María Ponce-Renilla ,&nbsp;Inmaculada Pereda-Pérez ,&nbsp;Cristina Izquierdo-Luengo ,&nbsp;Rosa María Tolón ,&nbsp;Fernando Berrendero","doi":"10.1016/j.nbd.2026.107300","DOIUrl":"10.1016/j.nbd.2026.107300","url":null,"abstract":"<div><div>Fear-related disorders, characterized by inappropriate learned fear and resistance to extinction, are among the most prevalent psychiatric conditions. Potential modifications in neurogenesis and brain activity were studied as possible individual factors associated with the development of these pathologies. By using Pavlovian fear conditioning and extinction paradigm, male and female mice were categorized in resilient and susceptible phenotypes based on their individual fear extinction behavior. Increased neurogenesis, as revealed by higher expression of the early neuronal marker doublecortin in the subgranular zone of the dentate gyrus, was observed in susceptible male and female mice. This result suggests the existence of a compensatory mechanism given that the DNA-alkylating agent temozolomide induced an impairment of fear extinction and a reduction of neurogenesis in male mice. The use of c-Fos immunofluorescence revealed several brain regions that were differently activated in susceptible animals, although these differences were less evident in female mice. Categorization by k-means clustering based on c-Fos labelling was significantly associated with phenotype of extinction in male, but not female, animals. Pairwise Pearson correlations between brain regions showed that resilience and susceptibility to fear extinction are related to divergent circuit-level reorganizations. These findings reveal new individual factors involved in the variability of fear extinction response which could be of interest for the development of future therapeutic strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107300"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Argonaute2-associated small RNA profiles in microglia and neurons drive cell-specific responses in a mouse model of temporal lobe epilepsy","authors":"Leticia Villalba-Benito ,&nbsp;Justine Mathoux ,&nbsp;Theresa Auer ,&nbsp;Kaushik Narasimhan ,&nbsp;Ruth Colbert ,&nbsp;James P. Reynolds ,&nbsp;Elizabeth Brindley ,&nbsp;Aasia Batool ,&nbsp;Thomas D.M. Hill ,&nbsp;Mairead Diviney ,&nbsp;Morten T. VenØ ,&nbsp;Marco Prinz ,&nbsp;Niamh M.C. Connolly ,&nbsp;Dearbhaile Dooley ,&nbsp;David C. Henshall ,&nbsp;Gary P. Brennan","doi":"10.1016/j.nbd.2026.107284","DOIUrl":"10.1016/j.nbd.2026.107284","url":null,"abstract":"<div><div>Small RNAs including microRNAs (miRNAs) and tRNA fragments (tRFs) are key post-transcriptional regulators of gene expression in temporal lobe epilepsy (TLE), but the cellular origin of these changes is often unclear. Here, we dissected the cell-type specific small RNA landscape, focussing on miRNA and tRFs, during epileptogenesis and in chronic epilepsy by profiling the RNA-induced silencing complex (RISC) using novel, transgenic mice with inducible expression of a FLAG-tagged Argonaute 2 protein driven specifically in neurons (Thy1-Ago2) or microglia (Cx3cr1-Ago2). We induced epilepsy in male mice via intra-amygdala microinjection of kainic acid and tracked miRNA expression over time in the hippocampus. Microglia and neurons displayed distinct and largely non-overlapping small RNA profiles across disease. Shortly following the epileptogenic insult, we detected a rapid microglial miRNA and tRF response which was sustained in chronic stages of the disease whereas small RNA changes in neurons displayed a delayed but sustained wave of unique changes as the disease progressed. Interestingly, our data reveals selective loading and incorporation of miRNAs into Ago2/RISC complexes, independent of overall abundance, in a cell- and disease-stage specific manner as well as differential processing of tRNAs in microglia compared to neurons. Additionally we found that certain epilepsy-associated miRNAs, previously considered ubiquitous, display dysregulation in multiple cell types while exhibiting cell-specific activity. Together our results demonstrate the cell-specific small RNA responses and functions to epileptogenic insults and shed further light on the complexity of post-transcriptional gene dysregulation in TLE. The findings indicate the potential advantages of targeted, cell-specific therapeutic strategies to effectively modulate miRNA pathways in epilepsy.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107284"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The neuropathological mechanisms underlying the inborn errors of lysine metabolism","authors":"Ye Guo ,&nbsp;Junjie Wu ,&nbsp;Weixiang Guo","doi":"10.1016/j.nbd.2026.107315","DOIUrl":"10.1016/j.nbd.2026.107315","url":null,"abstract":"<div><div>Optimal lysine catabolism is essential for the proper growth and development of mammals. Lysine is degraded through either the saccharopine or pipecolate pathway, processes characterized by distinct tissue specificity and subcellular compartmentalization. Although controversy persists, accumulating evidence suggests that the saccharopine pathway serves as the predominant route for lysine degradation in the mammalian brain. Pathogenic variants of genes encoding the enzymes involved in lysine catabolism lead to severe inborn errors of metabolism, including hyperlysinemia-II, pyridoxine-dependent epilepsy-<em>ALDH7A1</em>, and glutaric aciduria type I, which are biochemically characterized by the systemic accumulation of neurotoxic metabolites. Patients with the aforementioned disorders exhibit apparent neurological symptoms, ranging from cognitive impairment to severe encephalopathy, indicating that the dysregulation of lysine metabolism has deteriorative impacts on brain development and function. It is worth noting that a subset of patients still suffers from developmental delay and chronic neurological dysfunction, despite the amelioration of acute seizures or encephalopathic crises resulting from a combination of a lysine-restricted diet and pharmacotherapy. This elusive neuropathology has prompted increasing research aimed at identifying the pivotal regulatory roles of enzymes in neural functions and the neurotoxic effects of lysine metabolites in the brain. Here, we summarize current insights into the pathogenic mechanisms underlying the neurological manifestations of lysine metabolism disorders. A comprehensive understanding of the association between biochemical abnormalities and neurometabolic deficiencies has profound implications for refining therapeutic strategies to improve neurodevelopmental outcomes in affected patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107315"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of the LHb glutamatergic pathway ameliorates depressive-like behaviors in a 6-hydroxydopamine-induced Parkinson's disease mouse model","authors":"Juntao Cui,&nbsp;Di Zhao,&nbsp;Junchao Liu,&nbsp;Junliang Qian,&nbsp;Jun Wang,&nbsp;Limin Shi","doi":"10.1016/j.nbd.2026.107293","DOIUrl":"10.1016/j.nbd.2026.107293","url":null,"abstract":"<div><h3>Background</h3><div>Depression is one of the most common non-motor disorders and neuropsychiatric comorbidities in Parkinson's disease (PD). The pathophysiology of depression in PD patients remains unclear and has been largely unexplored.</div></div><div><h3>Method</h3><div>In this study, we employed chemogenetics and pharmacology to modulate the lateral habenula (LHb) and its downstream brain regions, the rostromedial tegmental nucleus (RMTg) and the ventral tegmental area (VTA) in wild type (WT) and 6-hydroxydopamine (6-OHDA) mice, to investigate the potential mechanisms underlying the improvement of PD-related depression.</div></div><div><h3>Results</h3><div>Inhibition of LHb glutamatergic neurons, as well as disruption of the LHb-RMTg pathway, along with inhibition of RMTg GABAergic neurons ameliorates depressive-like behavior in 6-OHDA mice. Conversely, activation of LHb glutamatergic neurons, the LHb-RMTg pathway, and activation of RMTg GABAergic neurons exacerbated depressive-like behavior in WT and 6-OHDA mice. Notably, either inhibition or activation of the LHb-VTA pathway did not produce any significant changes in depressive-like behavior in WT and 6-OHDA mice. Additionally, activation of VTA DAergic neurons effectively ameliorating depressive-like behavior in 6-OHDA mice.</div></div><div><h3>Conclusions</h3><div>Inhibition of the LHb glutamatergic pathway ameliorates depressive-like behaviors in 6-OHDA PD mice model. These findings offer new insights for advancing research and developing novel treatments for PD-related depression.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107293"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultra-high-field (9.4 T) ex vivo diffusion MRI tractography reveals microstructural differences in Parkinson's disease motor subtypes","authors":"Jackson Boonstra ,&nbsp;Stijn Michielse ,&nbsp;Yasin Temel ,&nbsp;Ali Jahanshahi ,&nbsp;Alard Roebroeck","doi":"10.1016/j.nbd.2026.107266","DOIUrl":"10.1016/j.nbd.2026.107266","url":null,"abstract":"<div><div>The structural correlates of Parkinson's disease (PD) with tremor-dominance and those with non-tremor dominance are not fully differentiated. Ultra-high field magnetic resonance imaging (UHF-MRI) allows the human brain to be imaged at a higher resolution compared to traditional scanner strengths but has largely been underutilized in PD research. Scanning post-mortem tissue allows for increased scan times and fewer movement issues leading to improved image quality, especially higher spatial resolution. We performed diffusion MRI on twelve post-mortem hemispheres (eight parkinsonian (four tremor-dominant, four non-tremor-dominant) and four non-demented controls) scanned with a specialized 9.4 Tesla human post-mortem brain coil. Diffusion tensor analysis was performed for local scalar diffusion metrics and constrained spherical deconvolution tractography was performed for global connectivity metrics. Compared to both non-tremor-dominant patients and controls, tremor-dominant patients displayed greater hemispheric fractional anisotropy. While motor subtypes were similar to each other across multiple regional diffusion metrics, each subtype demonstrated subtype-specific differences when compared to controls. Interconnections within basal ganglia circuitry mainly involving the internal capsule showed disparities across both subtypes and controls. Our findings show motor subtype specific circuitopathies in PD and improve the mapping of connectivity fingerprints potentially relevant in the planning of treatment regimes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107266"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The M1-like microglia-A1-like astrocyte Axis: A central hub linking BDNF dysregulation in chronic stress to anxiety disorders","authors":"Hongguo Li,&nbsp;Yuchen Zhu,&nbsp;Peijie Liu,&nbsp;Siqi Song,&nbsp;Xiping Zhang,&nbsp;Chenxu Liu,&nbsp;Minghui Hu,&nbsp;Yao Zhang,&nbsp;Chaojie Wang,&nbsp;Yushi Hu","doi":"10.1016/j.nbd.2026.107278","DOIUrl":"10.1016/j.nbd.2026.107278","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The high global prevalence of anxiety disorders, coupled with the limitations of existing treatments, constitutes a severe public health challenge. Chronic stress, as a core environmental trigger, has garnered increasing attention for its mechanism of mediating brain-derived neurotrophic factor (BDNF) imbalance through neuroinflammation. BDNF dysregulation may contribute to anxiety disorders, particularly in subtypes with heightened neuroinflammation. The objective of this review is to comprehensively and methodically explores the potential role of the “M1-like microglia-A1-like astrocyte axis (M1-A1 axis)” in linking chronic stress to BDNF dysregulation in anxiety disorders, and to provide a theoretical basis for intervention strategies targeting this axis. By synthesizing recent relevant clinical and preclinical evidence, this review integrates evidence from molecular to systems levels, focusing on the activation mechanisms of neuroinflammation under chronic stress, the crosstalk between glial cells, and their regulatory network on BDNF. Chronic stress is associated with peripheral and central cascades through hypothalamic-pituitary-adrenal (HPA) axis activation and gut microbiota disruption. Within the central nervous system (CNS), stress induces microglial polarization toward the pro-inflammatory microglial subpopulations (hereinafter referred to as M1-like microglia). The signals released by M1-like microglia, such as Interleukin-1 alpha (IL-1α), Tumor Necrosis Factor-alpha (TNF-α), and Complement Component 1q (C1q) (ITC), drive astrocytes to transform into the neurotoxic astrocyte states (hereinafter referred to as A1-like astrocyte), forming the “M1-A1 axis”. This axis contributes to BDNF dysregulation through the following mechanisms: (1) Release of pro-inflammatory cytokines inhibits BDNF transcription and translation; (2) Induction of astrocytic lactate metabolism disruption, which impairs neuronal energy supply and acidifies the microenvironment, further amplifying inflammation and affecting BDNF expression; (3) Compromise of the blood-brain barrier(&lt;em&gt;BBB&lt;/em&gt;)enables peripheral immune cells to penetrate into the CNS, and these cells work in synergy with central glial cells to amplify inflammation. The reduction in BDNF and the imbalance in the ratio of its precursor to mature form ultimately lead to impaired synaptic plasticity in brain regions like the hippocampus (HIP) and amygdala, precipitating anxiety-like behaviors. Existing pharmacological interventions are inadequate to reverse this pathological process. The M1-A1 axis may serve as a key node linking chronic stress to BDNF dysregulation and anxiety disorders. Targeting the phenotypic transformation of glial cells, repairing the BBB, or modulating glial cell metabolism (e.g., lactate shuttle) may represent potential strategies&lt;!--&gt; &lt;!--&gt; requiring further validation. Future research should focus on the spatiotemporal dynamics of this axis and its clinical translatio","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107278"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic disruption of leucine rich repeat transmembrane protein 4 like 1 induces a pro-social behavioural phenotype in zebrafish","authors":"Courtney Hillman ,&nbsp;Giulia Petracco ,&nbsp;Barbara D. Fontana ,&nbsp;María Florencia Scaia ,&nbsp;Elisa Dalla-Vecchia ,&nbsp;Jon H. Wetton ,&nbsp;William H.J. Norton ,&nbsp;Matthew O. Parker ,&nbsp;Florian Reichmann","doi":"10.1016/j.nbd.2025.107251","DOIUrl":"10.1016/j.nbd.2025.107251","url":null,"abstract":"<div><h3>Background</h3><div>In humans, disruptions in social behaviour are characteristic of many neuropsychiatric disorders, where both genetic risk factors and synaptic dysfunctions can contribute to the phenotype. Among the genes implicated in synaptic regulation, the synaptic adhesion protein leucine-rich repeat transmembrane protein 4 (LRRTM4) has been identified as a key player in maintaining synaptic function and neuronal circuit integrity. However, the potential involvement of LRRTM4 in modulating social behaviour and its contribution to social deficits has yet to be explored.</div></div><div><h3>Methods</h3><div>In the current study, we used zebrafish to study how deficiency in <em>lrrtm4l1</em>, a zebrafish orthologue of <em>LRRTM4</em>, affects sociality. For this, the social behaviour of homozygous <em>lrrtm4l1</em>^{<em>−/−</em>} mutant zebrafish was analysed in multiple behavioural assays and the brain transcriptome of mutant animals was investigated by RNAseq.</div></div><div><h3>Results</h3><div>Mutant zebrafish displayed a pro-social phenotype in multiple behavioural assays. Groups of <em>lrrtm4l1</em>^−/− zebrafish formed more cohesive shoals and mutant individuals spent more time in the vicinity of conspecifics during a social interaction test. They were also less aggressive and in contrast to wild-type zebrafish did not differentiate in their interactions with known and unknown groups of fish. Neurotranscriptomic analysis revealed 560 differentially expressed genes including changes in glutamatergic neurotransmitter signalling, tryptophan-kynurenine metabolism and synaptic plasticity.</div></div><div><h3>Conclusion</h3><div>These findings suggest that <em>lrrtm4l1</em> is an important regulator of social behaviour in zebrafish. In a translational perspective, LRRTM4 is a promising potential therapeutic target that warrants further investigation in the framework of neuropsychiatric conditions characterized by major social impairments.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107251"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}