Prenatally elevated glucocorticoid disrupts social behavior via GR-Id3/E47-dependent astroglial dysfunction in LPS-induced autism-like rats.

Maternal infection during pregnancy may contribute to autism spectrum disorder (ASD) through dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, however, the precise mechanisms disrupting fetal neurodevelopment remain unclear. By integrating human cohort analyses with experimental models, this study identifies prenatal infection as a significant maternal risk factor associated with elevated glucocorticoid (GC) exposure in offspring. In animal model, maternal lipopolysaccharide (LPS) exposure induced fetal GC surges, leading to GC receptor (GR)-dependent upregulation of inhibitor of DNA binding 3(Id3). Elevated Id3 formed complexes with E47, impairing its suppression of the astrocytic gene S100b and promoting aberrant astroglial differentiation. This astrocytic dysfunction disrupted synaptic glutamate/GABA homeostasis, resulting in core autistic-like behavioral phenotypes. Importantly, prenatal pharmacologic inhibition of GR signaling or downregulation of Id3 rescued Id3-E47 functional equilibrium, normalized astrocytic differentiation, and attenuated behavioral deficits. Our findings establish the GC-GR-Id3/E47 pathway as a mechanistic link between prenatal environmental insults and neurodevelopmental pathology, providing novel etiological insights into an ASD subtype of gestational infection.