Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and cortical ESR1 mRNA is associated with schizophrenia. In a small case–control genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single-nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (P = 0.01–0.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P = 0.01–0.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the ‘at risk’ PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenia. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3′ haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.

By using improved methods for in situ hybridization to detect expression of androgen receptor (AR) mRNA, the distribution of expression was mapped in the adult male zebra finch brain. In the neural song circuit, robust expression was found in area X of the lobus parolfactorius (LPO) as well as in other song regions previously reported. Expression was also found in many areas of the hypothalamus and dorsal thalamic nuclei, nucleus intercollicularis and ventricular areas of the midbrain, cerebellar Purkinje and granule cells, the hyperstriatum, medial neostriatum, medial LPO, and archistriatum. In juvenile males, AR mRNA expression was first detected in nucleus high vocal center (HVC) at posthatch day 9 (P9), in area X at P9-P11, and in the region of the robust nucleus (RA) in the medial archistriatum by P7. Estrogen treatment of hatchling females caused an increase in the expression of AR mRNA in HVC and area X by P11, whereas treatment of hatchling males with the aromatase inhibitor fadrozole decreased the expression of AR mRNA at P11. The present results indicate that masculine development of AR expression begins in area X and HVC before they are thought to be synaptically connected, suggesting that different song nuclei initiate sexual differentiation independently of transsynaptic masculinizing influences. The present results suggest that estrogen is necessary for full masculine AR expression in the song system and that the estrogenic regulation of AR contributes to subsequent differential actions of androgen in male and female song nuclei.

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