24.4 SEX BIAS IN SEIZURE SUSCEPTIBILITY OF A MOUSE MODEL OF THE RISK GENE FOR AUTISM SPECTRUM DISORDER, CHD8

Abstract

Mutations in the chromatin remodeler CHD8 are highly associated with autism spectrum disorder (ASD), as well as a range of comorbidities such as sleep disorder and gastrointestinal complaints. In phenotyped cohorts of people carrying disruptive CHD8 mutations, 14% reported abnormal epileptiform activity including seizures. It is not yet known how disruptive mutations in CHD8 that lead to increased risk for ASD diagnosis affect the susceptibility for seizures. We utilized a mouse model of CHD8 haploinsufficiency, CHD8+/-. These mice have reduced CHD8 expression analogous to the loss of expression from disruptive changes in CHD8 in people. We observed behavioral seizures in CHD8+/- mice during handling and conducted longitudinal observations of mice in our colony. To assess for increased neurological excitability, we performed challenges using the proconvulsant GABAA inhibitor pentylenetetrazole (PTZ) in CHD8+/- and age-matched wild-type (WT) controls at 6, 11, and 13 months of age. Seizures were video recorded, and raters who were blinded to genotype and sex scored the seizure severity using a modified Racine scale. By late adulthood, approximately 40% of CHD8+/- male and female mice evidenced spontaneous generalized tonic-clonic (GTC) seizures of up to 4 minutes duration during handling, compared to 3.4% of WT littermates (p = 0.0007, 2-tailed Fisher’s exact test). Male CHD8+/- mice showed significantly increased seizure scores (p = 0.003, 2-sample student’s t test) after PTZ challenge compared to WT males at 11 months and 13 months of age, whereas female mice did not show an increased susceptibility to PTZ challenge at any age. The observation of spontaneous seizure incidence was not associated with premature death or weight loss. These data implicate CHD8 perturbation in the neurophysiological mechanisms leading to both ASD and seizures, which culminate in the onset of spontaneous GTC seizures in a subset of people carrying disruptive CHD8 mutations. This finding was replicated spontaneously in our mouse model, with GABAA antagonism revealing a sex-specific bias in seizure susceptibility. This finding has important implications for the future health of people carrying disruptive CHD8 mutations, and our genetic mouse model is a tractable system in which to examine precipitants and to test treatments that might alleviate seizures.