The “don’t eat me” signal CD47 is associated with microglial phagocytosis defects and autism-like behaviors in 16p11.2 deletion mice

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(16)

Опубликована: Апрель 16, 2025

Various pathological characteristics of autism spectrum disorder (ASD) stem from abnormalities in brain resident immune cells, specifically microglia, to prune unnecessary synapses or neural connections during early development. Animal models ASD exhibit an abundance different regions, which is strongly linked the appearance behaviors. Overexpression CD47 on neurons acts as a “don’t eat me” signal, safeguarding inappropriate pruning by microglia. Indeed, overexpression occurs 16p11.2 deletion carriers, causing decreased synaptic phagocytosis and manifestation characteristics. However, role impairment leading phenotypes mouse model unclear. Moreover, whether blocking can alleviate mice’s behavioral deficits remains unknown. Here, we demonstrate strong link between increased expression, microglia capacity, social novelty preference mice. The reduction caused rise excitatory transmission prefrontal cortex Importantly, using specific antibody reducing expression short hairpin RNA (shRNA) enhanced reduced transmission. Reduction improved These findings that associated with mice could be promising target for development treatment ASD.

Язык: Английский

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Integrative Single-Cell Analysis of Autism Spectrum Disorder Animal Models Reveal Convergent Transcriptomic Dysregulation Involved in Excitatory-Inhibitory Imbalance and Glial Disfunction

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Май 6, 2025

ABSTRACT Autism Spectrum Disorder (ASD) presents profound clinical and etiological heterogeneity, complicating the identification of core pathophysiological mechanisms. Single-cell RNA sequencing (scRNA-seq) offers cellular resolution but integrating findings across diverse studies remains challenging. Here, we constructed a unified single-cell reference framework by scRNA-seq data from 11 distinct genetic environmental ASD animal models, encompassing over 300.000 cells various brain regions developmental stages. Comparative analyses revealed convergent differentially expressed genes (DEGs) neuronal glial populations. Cross-model comparisons validated integration, showing significant concordance between dataset individual studies, particularly for populations, demonstrating how models like valproic acid exposure recapitulate some transcriptomic alterations seen in models. Cell communication support widespread excitatory-inhibitory imbalance with predicted signaling involving ligands Pdgfa Reln . Furthermore, identified dysfunction, notably downregulation crucial functional astrocytes signatures metabolic dysregulation mature oligodendrocytes. Cross-referencing SFARI database confirmed overlap high-confidence risk genes, notable dysregulated specific cell types included Ermn (upregulated multiple glia), Foxg1 (downregulated L5/6 NP neurons) Mef2c MEIS2-like interneurons). Comparison human postmortem conserved dysregulation, highlighting enrichment presynaptic/postsynaptic translation processes neurons (implicating CACNAIA , GRIN2B CAMK2A ribosomal proteins) along neurodevelopmental disorder pathways oligodendrocytes, NRXN DLGAP gene networks. This integrative study provides unprecedented insight into molecular pathologies underlying ASD, establishing valuable resource understanding shared mechanisms identifying new potential therapeutic targets.

Язык: Английский

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Overgrowth-intellectual disability disorders: progress in biology, patient advocacy and innovative therapies

Disease Models & Mechanisms, Год журнала: 2025, Номер 18(5)

Опубликована: Май 1, 2025

ABSTRACT Overgrowth-intellectual disability (OGID) syndromes encompass a group of rare neurodevelopmental disorders that frequently share common clinical presentations. Although the genetic causes many OGID are now known, we lack clear mechanistic understanding how such variants disrupt developmental processes and ultimately culminate in overgrowth neurological symptoms. Patient advocacy groups, as Overgrowth Syndromes Alliance (OSA), mobilising patients, families, clinicians researchers to work together towards deeper needs patients with OGID, well understand fundamental biology relevant genes, goal developing treatments. In this Review, summarise three encompassed by OSA, namely Sotos syndrome, Malan syndrome Tatton-Brown-Rahman syndrome. We discuss similarities differences behind each disorder explore future approaches could potentially provide way ameliorate some unmet OGID.

Язык: Английский

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Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling in autism

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Май 15, 2025

Autism spectrum disorder (ASD) is a complex neurodevelopmental characterized by persistent deficits in social communication and repetitive behaviors. Recent studies indicated that heterozygous mutations the mixed lineage leukemia 5 (MLL5) gene are implicated ASD susceptibility associated with abnormalities. However, detailed mechanisms remain unclear. Here, we demonstrate Mll5 haploinsufficiency mice impairs microglial phagocytosis, drives neuronal hyperexcitability, recapitulates core ASD-like We also show acts as an epigenetic regulator, modulating phagocytosis via TREM2-SGK3-GSK3β signaling axis, which deficient glucose metabolism. Furthermore, individual-derived microglia exhibit parallel reductions MLL5 expression phagocytic function. By targeting this pathway, lithium chloride, GSK3β inhibitor, rescues both behavioral abnormalities mice. Our findings highlight MLL5’s critical role its potential therapeutic target.

Язык: Английский

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Understanding autism: Causes, diagnosis, and advancing therapies

Brain Research Bulletin, Год журнала: 2025, Номер 227, С. 111411 - 111411

Опубликована: Май 29, 2025

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition marked by difficulties in social communication, languages, and repetitive behaviors. Its rising prevalence has made it critical global public health issue. ASD believed to arise from combination of genetic environmental influences. While some gene mutations associated with have been identified, most cases lack clear explanations. Evidence increasingly points early-life factors as key contributors ASD, including advanced parental age, maternal diabetes during pregnancy, infections, hormonal imbalances, certain medications, exposure air pollution. Currently, diagnosis relies on behavioral assessments, but the absence specific molecular biomarkers poses significant obstacles early detection targeted therapies. Encouragingly, research identified potential biomarkers, such neuroimaging classifiers, electroencephalography patterns, eye-tracking data, digital analytics, expression profiles, inflammatory chemokine markers, proteomic metabolomic gut microbiota characteristics. Potential therapeutical strategies under investigation include therapies, non-invasive brain stimulation, antioxidants, oxytocin, AVPR1a antagonists, PPAR agonists, mTOR inhibitors. This review explores across five areas: epidemiological trends, mechanisms, their roles, diagnostic therapeutic approaches.

Язык: Английский

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