Estradiol modulates neuronal network hyperexcitability in select NDD risk genes

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• The male bias in autism spectrum disorder (ASD) is not well understood.
• Sex hormones during neurodevelopment may influence ASD risk.
• Estrogen's protective role against ASD/NDD gene mutations is hypothesized.

Purpose of the Study:

• To investigate the protective effect of 17β-estradiol against mutations in ASD/NDD genes.
• To screen 36 ASD/NDD genes using human stem cells and zebrafish models.
• To analyze estradiol's impact on transcriptomic, circuit, and behavioral levels.

Main Methods:

• Dual-system, multi-modal screening of 36 ASD/NDD genes.
• Utilized human induced pluripotent stem cell (hiPSC) and larval zebrafish models.
• Assessed gene expression, network activity, and behavioral phenotypes.

Main Results:

• Estradiol demonstrated broad amelioration of ASD/NDD gene expression across all knockouts.
• Estradiol selectively reduced network hyperexcitability in specific ASD/NDD genes (ASH1L, SCN2A, ANK2, CACNA1G, SHANK3).
• ASH1L and SCN2A showed comprehensive estradiol rescue of molecular and behavioral phenotypes, including seizures in SCN2A mutants.

Conclusions:

• Estradiol plays a novel role in modulating network hyperexcitability associated with ASD/NDD gene mutations.
• Findings support a potential protective mechanism of estradiol in neurodevelopmental disorders.
• Estradiol's effects are gene- and modality-specific, highlighting complex interactions.