Repeated Exposure to Electroconvulsive Seizures Induces Autistic-like Pathology in Mice

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits, and excessive repetitive behaviors. While ASD has a strong genetic basis, growing evidence suggests that epileptic seizures may serve as environmental risk factors for ASD development. The high comorbidity between epilepsy and ASD (20–30%) suggests potential shared neurobiological mechanisms, yet the causal relationship remains poorly understood. To investigate the causal role of seizures in the development of ASD-like pathology, we exposed adolescent mice (3 weeks old) to electroconvulsive seizures (ECS) for 10 consecutive days. This repeated ECS exposure led to the emergence of autistic-like behaviors including significantly decreased sociability, increased repetitive self-grooming, enhanced marble burying behavior, and anxiety-like behaviors, without affecting general locomotor activity. Additionally, repeated exposure to ECS induced significant changes in glutamatergic neurotransmission in the mice’s prefrontal cortex and hippocampus, brain regions critically involved in social cognition and behavioral regulation. Interestingly, these changes occurred without alterations in other excitatory/inhibitory neuronal markers, suggesting a specific impact on glutamate receptor expression rather than a general disruption of excitatory/inhibitory balance. These findings suggest that repeated seizures may contribute to ASD-like symptoms by specifically affecting key glutamatergic neurotransmitter systems, providing insights into the neurobiological mechanisms underlying the comorbidity between epilepsy and autism. In addition, repeated ECS differentially regulated histone deacetylase (HDAC) transcripts in a region-specific manner and produced seizure-intensity-dependent transcriptomic signatures.