Maternal anti-collapsin response mediator protein 1 antibody inducing autism-like behaviors in offspring

Maternal autoantibodies targeting neural proteins represent a major environmental contributor to autism spectrum disorder (ASD). Although anti-collapsin response mediator protein 1 (CRMP1) antibodies (Abs) have been detected in mothers of ASD children, the pathogenic role of anti-CRMP1 Ab in ASD remains unclear. Here, we evaluated the ability of maternal anti-CRMP1 Ab to induce pathology in a mouse model. Using a cell-based assay, we found that maternal anti-CRMP1 Ab persisted throughout gestation and was detected in offspring serum on postnatal day 16. Exposed offspring exhibited delayed developmental milestones during the neonatal period. During adolescence, exposed mice buried more marbles, spent more time self-grooming and enhanced central zone exploration in the open field test without changes in elevated plus maze, suggesting increased repetitive stereotyped behaviors and sensory hyposensitivity. Transcriptomic analysis of the offspring cortex on postnatal day 30 revealed upregulation of positive regulation of cholinergic synaptic transmission and downregulation of pathways related to axon guidance and presynaptic membrane organization. We further confirmed that the expression of genes associated with presynaptic membrane organization ( Nrxn1 , Pten , Ptprd , Nlgn1 ) were significantly reduced, suggesting that anti-CRMP1 Ab interferes with axon development. In vitro, anti-CRMP1 Ab treatment induced more growth cone collapse in iPSC-derived immature neurons without affecting basic neurite morphology. Collectively, we demonstrate that maternal anti-CRMP1 Ab leads to ASD-like behaviors in offspring and induces more growth cone to disrupt early neurodevelopment, thereby establishing single maternal anti-CRMP1 Ab as an important pathogenic factor for ASD.