Prenatal Exposure To Valproic Acid Induces Increased Autism-Like Behaviors and Impairment of Learning and Memory Functions in Rat Offspring by Upregulating ADAM10 Expression

Neurochemical Research, Journal Year: 2025, Volume and Issue: 50(3)

Published: April 17, 2025

Autism spectrum disorder (ASD) involves a complex neurodevelopmental pathogenesis. A disintegrin and metalloproteinase 10 (ADAM10) plays crucial role in embryonic brain development neural network stability. This study aimed to investigate the influence of ADAM10 on excitation/inhibition (E/I) balance, autism-like behaviors, learning memory dysfunction rats prenatally exposed valproic acid (VPA) determine potential intervention strategies. The VPA-exposed group exhibited increased levels secreted amyloid precursor protein-α (sAPPα). Moreover, overexpression glutamate decarboxylase 1 N-methyl-D-aspartate receptors was observed. High-performance liquid chromatography-mass spectrometry revealed elevated glutamate, glutamine, γ-aminobutyric acid, as well an E/I imbalance VPA group. Additionally, narrower synaptic clefts postsynaptic density vesicles were Remarkably, intraperitoneal administration inhibitor during critical period significantly improved ASD-like behavior function rats. effectively reduced abnormally high sAPPα prefrontal cortex corrected abnormal balance. Thus, inhibiting may improve imbalance, alleviate core symptoms ASD, dysfunction. use represents therapeutic strategy for treating ASD patients with intellectual disabilities.

Language: Английский

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), Journal Year: 2025, Volume and Issue: unknown

Published: May 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.

Language: Английский