Estradiol modulates neuronal network hyperexcitability in select NDD risk genes
Sex hormone signaling during neurodevelopment may act as a modulator of risk for neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs). By conducting a systematic and multi-modal evaluation of estradiol effects across loss-of-function deletions in 36 functionally diverse, large-effect ASD/NDD genes in human induced pluripotent stem cell-derived neurons and larval zebrafish, we uncover convergent and divergent gene-by-estradiol interactions at the transcriptomic, circuit, and behavioral levels. Whereas estradiol partially ameliorates dysregulated expression signatures across all ASD/NDD gene knockouts examined, it selectively and rapidly dampens network hyperexcitability phenotypes in only a subset of ASD/NDD gene knockouts. Two genes, ASH1L and SCN2A, are particularly responsive to estradiol treatment, with dramatic rescue of molecular and cellular effects in human knockout neurons, coupled with behavioral phenotypes in larval zebrafish mutants. The seven most estradiol responsive genes show enhanced protein-protein interaction network connectivity, strong co-expression in specific postnatal time periods, and enrichment in upper-layer mature excitatory neurons. Altogether, we describe distinct estradiol rescue in different modalities, elucidating shared transcriptomic effects as well as gene-specific cellular and behavioral rescue in the context of loss of function mutations of select ASD/NDD genes.