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Published on: March 25, 2016
Maternal anti-collapsin response mediator protein 1 antibody inducing autism-like behaviors in offspring
Yue Pan1, Zhirong Yuan1, Zirui Chen1
1Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Insights
Maternal autoantibodies against collapsin response mediator protein 1 (CRMP1) can cause autism spectrum disorder (ASD)-like behaviors in offspring. These antibodies disrupt early neurodevelopment, establishing CRMP1 antibodies as a pathogenic factor in ASD.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Maternal autoantibodies targeting neural proteins are linked to autism spectrum disorder (ASD).
- Anti-collapsin response mediator protein 1 (CRMP1) antibodies (Abs) are found in mothers of children with ASD, but their pathogenic role is unclear.
Purpose of the Study:
- To evaluate the pathogenic role of maternal anti-CRMP1 Abs in inducing ASD-like pathology in a mouse model.
- To investigate the effects of maternal anti-CRMP1 Abs on offspring neurodevelopment and behavior.
Main Methods:
- Maternal anti-CRMP1 Abs were administered to a mouse model.
- Offspring behavior was assessed using marble burying, self-grooming, open field, and elevated plus maze tests.
- Transcriptomic analysis of offspring cortex and in vitro studies on iPSC-derived neurons were performed.
Main Results:
- Maternal anti-CRMP1 Abs persisted in offspring and were associated with delayed developmental milestones.
- Adolescent offspring exhibited increased repetitive behaviors and sensory hyposensitivity.
- Transcriptomic analysis revealed altered pathways related to axon guidance and presynaptic organization, with reduced expression of key genes.
- In vitro, anti-CRMP1 Abs induced growth cone collapse in immature neurons.
Conclusions:
- Maternal anti-CRMP1 Abs induce ASD-like behaviors and disrupt early neurodevelopment in offspring.
- Anti-CRMP1 Abs interfere with axon development by affecting presynaptic membrane organization.
- Maternal anti-CRMP1 Abs are identified as a significant pathogenic factor in ASD.
Abstract:
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.
