Autism spectrum disorders (ASD) are much more common in males than in females. Molecular alterations within the estrogen receptor (ER) signaling pathway may contribute to the sex difference in ASD, but the extent of such abnormalities in the brain is not known. Postmortem middle frontal gyrus tissues (13 ASD and 13 control subjects) were used. The protein levels were examined by western blotting. The gene expression was determined by qRT-PCR. Gene expression analysis identified a 35% decrease in ERβ mRNA expression in the middle frontal gyrus of ASD subjects. In addition, a 38% reduction in aromatase (CYP19A1) mRNA expression was observed in ASD subjects. We also found significant decreases in ER co-activators that included a 34% decrease in SRC-1, a 77% decrease in CBP, and a 52% decrease in P/CAF mRNA levels in ASD subjects relative to controls. There were no differences in the mRNA levels of TIF-2, AIB-1 (ER co-activators), ER co-repressors (SMRT and nCoR) and ERα in the middle frontal gyrus of ASD subjects as compared to controls. We observed significant correlations between ERβ, CYP19A1, and co-activators in the study subjects. Immunoblot analysis further confirmed the changes in ERβ and aromatase at the protein level in the control and ASD subjects. These results, for the first time, provide the evidence of the dysregulation of ERβ and co-factors in the brain of subjects with ASD.

Estrogens, the primary female sex hormones, were originally characterized through their important role in sexual maturation and reproduction. However, recent studies have shown that estrogens play critical roles in a number of brain functions, including cognition, learning and memory, neurodevelopment, and adult neuroplasticity. A number of studies from both clinical as well as preclinical research suggest a protective role of estrogen in neurodevelopmental disorders including autism spectrum disorder (ASD) and schizophrenia. Alterations in the levels of estrogen receptors have been found in subjects with ASD or schizophrenia, and adjunctive estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia. This review summarizes the findings on the role of estrogen in the pathophysiology of neurodevelopmental disorders with a focus on ASD and schizophrenia. We also discuss the potential of estrogen as a therapeutic target in the above disorders.