Estradiol modulates neuronal network hyperexcitability in select NDD risk genes

The biological basis for the male sex bias in autism spectrum disorder (ASD) is poorly understood. Differential exposure to sex hormones during neurodevelopment has been proposed as a potential modulator of risk. To test the hypothesis that early exposure to the principal biologically active estrogen, 17β-estradiol, confers a protective effect against mutations in ASD and neurodevelopmental disorder (NDD) genes, we conduct a dual-system multi-modal screen of 36 functionally diverse, large-effect ASD/NDD genes in human induced pluripotent stem cell and larval zebrafish models. We uncover estradiol-dependent effects across genes and modalities, revealing convergent and divergent gene-by-estradiol interactions at the transcriptomic, circuit, and behavioral levels. Estradiol broadly ameliorates ASD/NDD gene expression patterns across all knockouts examined and selectively dampens network hyperexcitability phenotypes in human neurons and zebrafish brains in a subset of ASD/NDD genes (<i>ASH1L</i>, <i>SCN2A, ANK2, CACNA1G, SHANK3)</i>. Two genes, <i>ASH1L</i> and <i>SCN2A</i>, show comprehensive estradiol rescue of differential gene expression and network bursting activity in human neurons as well as sleep-wake and visual-startle phenotypes in larval zebrafish mutants. Moreover, estradiol rescues seizures and regional increases in brain activity in <i>SCN2A</i> larval zebrafish mutants. Altogether, we describe novel roles of estradiol in modulating network hyperexcitability in the context of loss of function mutations of select ASD/NDD genes.