Cellular and Molecular Neurobiology最新文献

{"title":"Causal Relationship Between Circulating Leukocyte Characteristics and Immune Cell Traits With Multiple Sclerosis Risk: A Two-Sample Bidirectional Mendelian Randomisation Study.","authors":"Jia-Jia Yun, Ya-Lei Li, Jing-Man Qiu, Yu Yang, Dan-Tong Han, Xiao-Han Yang, Chao Lv, Chao Ren","doi":"10.1007/s10571-026-01777-9","DOIUrl":"10.1007/s10571-026-01777-9","url":null,"abstract":"<p><p>The present study aimed to investigate MR-based evidence for potential causal relationships between circulating leukocytes, immune cell traits, and multiple sclerosis (MS) using a two-sample, bidirectional Mendelian randomisation (MR) approach. We analysed summary-level data from large-scale genome-wide association studies conducted by the International Multiple Sclerosis Genetics Consortium, the Blood Cell Consortium, and Immune Cell traits. Using inverse variance weighted (IVW), weighted mode, weighted median, simple mode, and MR-Egger methods, we estimated genetically predicted associations. The MR-Egger intercept assessed horizontal pleiotropy, Cochran's Q test examined genetic heterogeneity, and leave-one-out procedures evaluated the sensitivity of the results. We adjusted for multiple comparisons using the false discovery rate (FDR). Forward MR analysis using IVW as the primary method revealed associations between increased white blood cell count (OR = 1.16, 95% CI = 1.05-1.29, P = 0.004, P_FDR = 0.031) and lymphocyte count (OR = 1.18, 95% CI = 1.06-1.31, P = 0.003, P_FDR = 0.035) with a higher risk of developing MS. Conversely, the CD25hi CD45RA-CD4 not Treg %CD4+ (OR = 0.87, 95% CI = 0.808-0.942, P = 0.0005, P_FDR = 0.075) and the CD16-CD56 on HLA DR+ NK (OR = 0.85, 95% CI = 0.780-0.935, P = 0.0007, P_FDR = 0.093) were associated with a reduced risk of MS. In reverse MR analyses, MS showed no robust evidence of a causal effect on white blood cell or lymphocyte counts. Although an FDR-significant reverse association was observed for the IgD+ CD38 + B-cell absolute count subtype, leave-one-out sensitivity analysis indicated instability. Therefore, this finding was not considered reliable evidence of reverse causality. Genetic predisposition to increased white blood cell and lymphocyte counts elevates the risk of MS, while certain immune cell traits may reduce this risk.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human iPSC-Derived Spinal Neurons Carrying the ALS FUS (P525L) Mutation Exhibit Lower Response to Inhibitory Neurotransmitters.","authors":"Tiziano D'Andrea, Maria Cristina Benedetti, Michela Mochi, Valeria De Turris, Alessandro Rosa, Sergio Fucile","doi":"10.1007/s10571-026-01773-z","DOIUrl":"10.1007/s10571-026-01773-z","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder characterized by motoneurons degeneration. Functional studies have linked ALS to hyperexcitability and excitotoxicity, but the cause of the disease is unknown, though familial ALS cases are linked to pathogenic variants in several genes, including SOD1, TARDBP and FUS. Here we focused on the effect of the severe FUS (P525L) mutation on the functional properties of human spinal neurons derived from induced pluripotent stem cells (hiPSCs). This mutation delayed functional maturation, as revealed by the observation that mutated neurons showed alterations of membrane potential, reduced spontaneous synaptic activity, and altered action potentials at early differentiation stages. FUS (P525L) mutation was associated with a significant alteration of inhibitory signalling transmission: mutated neurons showed a significantly lower current response to GABA and glycine compared to control isogenic WT neurons of the same age. Also, glutamatergic currents exhibited a different temporal evolution in control and mutated neurons, but at a lower extent in comparison to inhibitory neurotransmitters. The decrease in the glycine-evoked currents was confirmed by the reduction of the expression of the α1 subunit of glycine receptor, measured by immunofluorescence assay. Similar functional alterations were measured in spinal neurons differentiated form a second hiPSC line, confirming the causative role of the FUS (P525L) mutation. Our data indicate that the FUS (P525L) mutation reduces the maturation rates and the function of hiPSC-derived spinal neurons, with a strong decrease of inhibitory transmission, which may affect the excitatory/inhibitory balance, possibly predisposing to excitotoxicity and neurodegeneration.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glial Cysteine Cathepsins: From Homeostasis to Neurodegeneration.","authors":"Anja Suhadolc, Selena Horvat, Janko Kos, Anja Pišlar","doi":"10.1007/s10571-026-01776-w","DOIUrl":"10.1007/s10571-026-01776-w","url":null,"abstract":"<p><p>Glial cells, namely microglia, astrocytes, and oligodendrocytes, play crucial roles in maintaining homeostasis in the central nervous system and orchestrating responses to injury, infection, and disease. Among the molecular regulators of glial function, cysteine cathepsins have emerged as key modulators of both physiological and pathological processes. These lysosomal peptidases are traditionally known for their housekeeping roles in protein degradation; however, accumulating evidence highlights their broader involvement in antigen presentation, microglial and astrocyte reactivity, inflammatory signalling, apoptosis, and myelination. Under normal conditions, cysteine cathepsins support essential functions in the central nervous system, including immune surveillance and tissue remodelling. Conversely, their dysregulation, characterized by overexpression, increased enzymatic activity, or mislocalization, can promote neuroinflammation and neurodegeneration, contributing to the pathogenesis of disorders such as Alzheimer's disease and multiple sclerosis. This review provides a comprehensive synthesis specifically focused on the diverse roles of cysteine cathepsins across major glial cell types, systematically summarizing current knowledge in microglia, astrocytes, and oligodendrocytes. We emphasize their cell type-specific, context-dependent, protective, and deleterious functions. Furthermore, we discuss mechanistic links between cysteine cathepsin activity and neurodegenerative processes and evaluate the therapeutic potential and current limitations of selectively targeting glial cysteine cathepsins. A deeper understanding of the context-dependent dual roles of these enzymes in brain physiology and pathology is critical for designing targeted interventions that could mitigate neuroinflammation and neurodegeneration.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fingolimod Acutely Facilitates the Activation of TRKB in a BDNF-dependent Manner.","authors":"Cecilia Anna Brunello, Paula Pastor Muñoz, José Pedro Araujo, Nina Seiffert, Katja Kaurinkoski, Plinio Casarotto, Caroline Biojone, Eero Castrén","doi":"10.1007/s10571-026-01774-y","DOIUrl":"10.1007/s10571-026-01774-y","url":null,"abstract":"<p><p>Fingolimod (FNG) is a sphingosine-1-phosphate receptor agonist currently prescribed for the treatment of remitting-relapsing multiple sclerosis. However, an increasing body of evidence indicates that FNG has a variety of other effects on the central nervous system, making it a good candidate to target other brain disorders that display loss of neuronal cells and synaptic plasticity. FNG treatments induce production of brain-derived neurotrophic factor (BDNF), which promotes neuronal plasticity, arborization and survival via signaling through its cognate receptor TRKB. In this study we characterize the relationship between FNG and TRKB in vitro and in vivo following acute treatments. We found that FNG induces TRKB activation in primary neuronal cultures in a BDNF-dependent way, indicating a rapid effect of FNG. This effect is different from the one elicited by antidepressants and is likely mediated by modulation of plasma membrane properties, as the enhancement of fluoxetine binding and dimerization of the cholesterol-insensitive TRKB mutant Y433F mimic the effects of cholesterol. Moreover, acute FNG treatment normalizes the generalization of conditioned fear response seen in heterozygous BDNF null female mice without affecting the wild-type littermates. Taken together, our data indicate that FNG allosterically promotes TRKB signaling and thereby induces the increase in BDNF production, which mediates the therapeutic effects of the drug on neuronal plasticity.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Hydroxybutyrate Exposure is Associated with Increased TH⁺ Neuron Abundance and Dopaminergic-Related Transcriptional Features in Human Midbrain Organoids.","authors":"Juan Jair Santillán-Cigales, Cesar Meléndez-Ramírez, Margareht Reyes-Aldana, Itzel Escobedo-Avila, Maricela Cabrera-Castro, Alejandro López-Saavedra, Raquel Cuevas-Diaz Duran, Iván Velasco","doi":"10.1007/s10571-026-01771-1","DOIUrl":"10.1007/s10571-026-01771-1","url":null,"abstract":"<p><p>Neuronal differentiation is a highly regulated process in which morphogens establish cellular identities through coordinated transcriptional programs. However, the contribution of physiologically derived metabolites to human neural development remains poorly understood. β-hydroxybutyrate (bhb) has been recognized as an inflammatory, epigenetic, energetic, and neuroprotective regulator. We differentiated midbrain floor plate neural precursor cells (mfNPC) from human embryonic stem cells to generate midbrain organoids (MBOs), which were exposed to bhb. Although dopaminergic differentiation occurred in control MBOs, treatment with 1 mM bhb for 16 days significantly increased both the number of Tyrosine hydroxylase-positive (TH⁺) neurons, and the corresponding transcripts assessed by bulk RNA sequencing. Such transcriptomic profiling revealed modest but consistent bhb-associated changes in trophic, neuronal and dopaminergic transcripts. To further characterize these changes, we performed gene set enrichment analysis using curated cell phenotypes-associated transcriptional programs. These analyses indicated that bhb treatment is associated with shifts in the enrichment scores of dopaminergic programs in day 16 MBOs. At the epigenomic level, we used CUT&RUN assays to map H3K27 acetylation, and the selected candidates H3K27ac regions after bhb treatment were linked to their closest neighboring genes, suggesting positive enrichment of neural and dopaminergic gene ontology categories at both time points. Unsupervised analysis of H3K27ac-enriched regions revealed three major clusters detected across differentiation, although present in both control and bhb-treated MBOs. Motif enrichment analysis of clustering regions identified distinct predicted transcription factor binding motifs in mfNPC and MBOs. Finally, we integrated this motif analysis, enhancer annotation, and our transcriptomic data on a web platform, Enhancer Network Explorer, to explore relationships between H3K27ac profiles, transcriptional changes and bhb exposure during human MBOs differentiation. Together, our results indicate that bhb treatment is associated with increased TH-positive cell abundance and with population-level changes related to neurodevelopmental transcriptional programs. These findings suggest that bhb might support early human midbrain differentiation and provide a starting point for future studies addressing the mechanisms linking metabolic cues, chromatin-associated regulation and dopaminergic differentiation.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Diagnostic and Therapeutic Value of Micro-RNA in Parkinson's Disease.","authors":"Guo-Liang Lin, Yue Wang, Bi-Huan Cheng","doi":"10.1007/s10571-026-01767-x","DOIUrl":"10.1007/s10571-026-01767-x","url":null,"abstract":"<p><p>The pathogenesis of Parkinson's disease (PD) remains incompletely understood, and effective early diagnostic biomarkers and disease-modifying therapies are lacking. MicroRNAs (miRNAs), a class of small non-coding RNAs, have emerged as critical regulators of gene expression involved in key pathological processes of PD, including neuronal apoptosis, mitochondrial dysfunction, oxidative stress, and α-synuclein (α-syn) aggregation. Recent evidence suggests that dysregulated miRNAs expression contributes significantly to PD progression and may serve as minimally invasive biomarkers for early diagnosis. Furthermore, miRNA-based therapeutic strategies offer promising avenues for targeting disease-related molecular pathways. This review summarizes the mechanistic roles of miRNAs in PD pathogenesis and highlights their potential clinical applications in diagnosis and therapy.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma Biomarkers for Alzheimer's Disease Across the Continuum: A Systematic Review of SIMOA-Based Studies.","authors":"María de Los Ángeles Fernández-Ceballos, José M Prieto-González, Roberto Carlos Agís-Balboa","doi":"10.1007/s10571-026-01752-4","DOIUrl":"10.1007/s10571-026-01752-4","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common cause of dementia, and its overall incidence is rising as the proportion of older individuals in the population increases. Traditional diagnostic methods, such as lumbar puncture and neuroimaging, are costly and invasive, driving the search for blood-based biomarkers (BBB) for early diagnosis. The quantification of these biomarkers requires ultrasensitive techniques, such as the single-molecule array (SIMOA) platform. This systematic review synthesizes the available evidence on the biomarkers β-amyloid (Aβ42, Aβ40, and their ratio), tau protein (t-Tau, p-Tau181, p-Tau231, p-Tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in studies analyzing their blood concentrations using SIMOA, regardless of the platform model (SR-X, HD-1, HD-X). Findings support the potential of plasma biomarkers as an alternative or complement to invasive methods, although further validation is required before clinical implementation.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Engineered Multifunctional Fusion Protein Targeting Aβ Oligomers, Microglia and Autophagy Ameliorates Cognitive Deficits and Amyloid Pathology in Alzheimer's Disease Mice.","authors":"Jie Zhu, Ya-Ru Huang, Fei Chen, Mei-Qi Wang, Xiao-Lin Yu, Gui-Feng Zhang, Rui-Tian Liu","doi":"10.1007/s10571-026-01753-3","DOIUrl":"10.1007/s10571-026-01753-3","url":null,"abstract":"<p><p>In Alzheimer's disease (AD), Amyloid-β (Aβ) oligomers function as key neurotoxic agents that underpin the disease's progression. A diverse array of therapeutic entities, including peptides, single-chain variable fragments (scFvs), and small molecules, have demonstrated the ability to interact with Aβ oligomers, thereby suppressing their aggregation and associated neurotoxicity. Despite these advances, such agents frequently struggle to promote the phagocytosis and subsequent breakdown of aggregated Aβ by microglia. Moreover, the dense accumulation of Aβ oligomers may resist enzymatic hydrolysis within the acidic lysosomal lumen, contributing to lysosomal stress and dysfunction. To overcome these problems, we engineered a multifunctional fusion protein, p62-LIR-W20-Tuftsin (W20-LT), consisting of an oligomer-specific scFv, a microglia-targeting Tuftsin peptide, and a p62-LIR peptide to activate autophagy. In vitro assays demonstrated that W20-LT significantly outperformed the parental W20 by promoting the rapid microglial uptake of Aβ oligomers and enhancing their intracellular clearance through an autophagy-associated pathway. In APPswe/PS1dE9 (APP/PS1) mice, a low-dose regimen (0.5 µg, every 3 days) of W20-LT, but not W20, significantly ameliorated cognitive deficits and reduced amyloid pathology. Mechanistically, W20-LT was associated with enhanced autophagy-lysosomal pathway activity, as indicated by increased LC3B-II and reduced p62 levels, together with downregulated CatD and LAMP1 levels, thereby mitigating neuroinflammation. In summary, our findings suggest that W20-LT represents a promising proof-of-concept therapeutic strategy that combines scFv-based Aβ oligomer recognition with enhanced autophagy-associated clearance, thereby mitigating AD pathology.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of miR-204 Drives NPTX1-Dependent Mitochondrial Dysfunction and Neuronal Degeneration in Alzheimer's Disease.","authors":"Tae-Young Ha, Seung Min Lim, Hyunjun Park, Keun-A Chang","doi":"10.1007/s10571-026-01769-9","DOIUrl":"10.1007/s10571-026-01769-9","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by progressive cognitive decline accompanied by synaptic dysfunction and neuronal loss. Dysregulation of specific microRNAs (miRNAs) has been increasingly implicated in AD pathogenesis, suggesting that miRNA-mediated regulatory pathways may represent important mechanisms underlying neuronal vulnerability. Here, we identified mmu-microRNA-204-5p (miR-204) as a critical regulator of neuronal survival that is markedly downregulated in the hippocampus of 5xFAD mice. Through integrated bioinformatics analysis and experimental validation, we established neuronal pentraxin-1 (NPTX1) as a direct post-transcriptional target of miR-204. In primary cultured neurons, exposure to Aβ₁₋₄₂ oligomer (oAβ) drove marked upregulation of NPTX1 and precipitated neuronal injury, manifested by aberrant reactive oxygen species (ROS) accumulation, collapse of mitochondrial membrane potential, diminished cell viability, and dendritic degeneration. Inhibition of miR-204 further exacerbated these pathological changes and engaged mitochondrial apoptotic signaling, as evidenced by Bax upregulation, cytochrome c release, and caspase-3 cleavage. Conversely, restoration of miR-204 expression or genetic knockdown of NPTX1 attenuated oxidative stress, preserved mitochondrial integrity, and restored neuronal survival. Collectively, our findings uncover a previously unrecognized miR-204-NPTX1 regulatory axis that governs mitochondrial integrity and apoptotic susceptibility in AD, highlighting miR-204 as a potential therapeutic target for AD and related oxidative stress-associated neurodegenerative disorders.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prdm15 Deficiency Results in Impaired Hippocampal Neurogenesis and Autism-Like Behaviors.","authors":"Qiwen Dong, Weiwei Xiao, Zheng Sun, Zhongsheng Sun, Yan Wang","doi":"10.1007/s10571-026-01770-2","DOIUrl":"10.1007/s10571-026-01770-2","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder, with epidemiological studies consistently reporting a rising prevalence worldwide. Our previous human genetic sequencing analysis identified PRDM15 (PRDI-BF1 (Positive regulatory domain I-binding factor 1) and RIZ1 (Retinoblastoma protein-interacting zinc finger 1) homologous domain-containing protein 15), a transcriptional regulator and a member of the PRDM family, as a novel candidate risk gene for ASD. However, its precise role in brain development and subsequent behavioral outcomes remains unclear. Here, we demonstrate that Prdm15 deficiency in mice recapitulates core autism-like behaviors, including increased repetitive grooming, deficits in social interaction, and impaired social recognition memory. Structural MRI (Magnetic resonance imaging) and histological analyses revealed abnormal hippocampal architecture, characterized by reduced neuronal density in the CA1 (Cornu Ammonis 1) subregion. Through single-cell RNA sequencing of the developing hippocampus in mice, we found that Prdm15 deficiency impaired neurogenic lineage differentiation, leading to an accumulation of neural stem cells and a concomitant reduction in mature neurons, which were associated with transcriptional alterations in these cells. Crucially, conditional ablation of Prdm15 specifically in neural stem/progenitor cells achieved by crossing Prdm15-floxed mice (Prdm15^fl/fl) with the Nestin-Cre strain, was sufficient to partially recapitulate the cellular and behavioral phenotypes observed in constitutive Prdm15-deficient mice. Collectively, our findings identify PRDM15 as a critical regulator of hippocampal neurogenesis and provide evidence that its dysfunction contributes to the pathogenesis of ASD-like behaviors in mice.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}