Prenatally elevated glucocorticoid disrupts social behavior via GR-Id3/E47-dependent astroglial dysfunction in...

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• Maternal infection during pregnancy is a potential risk factor for autism spectrum disorder (ASD).
• The precise mechanisms linking prenatal infection to fetal neurodevelopmental disruptions, particularly involving the hypothalamic-pituitary-adrenal (HPA) axis, remain largely unknown.
• Glucocorticoids (GCs) are key mediators of the stress response and can impact fetal development.

Purpose of the Study:

• To elucidate the mechanistic link between maternal infection during pregnancy and the development of autistic-like behaviors in offspring.
• To identify the specific molecular pathways, including the GC-GR-Id3/E47 pathway, involved in mediating the effects of prenatal infection on neurodevelopment.
• To explore potential therapeutic targets for mitigating the neurodevelopmental consequences of prenatal insults.

Main Methods:

• Integration of human cohort analyses with experimental animal models (e.g., lipopolysaccharide exposure in pregnant mice).
• Measurement of glucocorticoid levels and analysis of gene expression (e.g., Id3, S100b) and protein interactions (Id3/E47 complex).
• Assessment of astrocytic differentiation, synaptic homeostasis (glutamate/GABA), and behavioral phenotypes in offspring.

Main Results:

• Prenatal infection, modeled by lipopolysaccharide (LPS) exposure, led to elevated fetal glucocorticoid (GC) surges.
• GC exposure upregulated inhibitor of DNA binding 3 (Id3) in a GC receptor (GR)-dependent manner, forming complexes with E47.
• This pathway disrupted astrocytic differentiation and synaptic glutamate/GABA homeostasis, causing autistic-like behaviors, which were rescued by inhibiting GR signaling or downregulating Id3.

Conclusions:

• The GC-GR-Id3/E47 pathway serves as a critical mechanistic link between prenatal environmental insults (maternal infection) and neurodevelopmental pathology, specifically contributing to an ASD subtype.
• Aberrant astroglial differentiation and disrupted synaptic homeostasis are key consequences of this pathway activation.
• Targeting the GC-GR-Id3/E47 pathway offers a potential therapeutic strategy for preventing or treating neurodevelopmental deficits associated with gestational infections.