Gene expression profiling identifies key estradiol targets in the frontal cortex of the rat

Estradiol modulates a wide range of neural functions in the frontal cerebral cortex where subsets of neurons express estrogen receptor-alpha and -beta. Through these receptors, estradiol contributes to the maintenance of normal operation of the frontal cortex. During the decline of gonadal hormones, the frequency of neurological and psychiatric disorders increases. To shed light on the etiology of disorders related to declining levels of estrogens, we studied the genomic responses to estradiol. Ovariectomized rats were treated with a sc injection of estradiol. Twenty-four hours later, samples from the frontal cortices were dissected, and their mRNA content was analyzed. One hundred thirty-six estradiol-regulated transcripts were identified on Rat 230 2.0 Expression Array. Of the 136 estrogen-regulated genes, 26 and 36 genes encoded proteins involved in the regulation of transcription and signal transduction, respectively. Thirteen genes were related to the calcium signaling pathway. They comprised five genes coding for neurotransmitter receptors. Transcription of three neuropeptides, including cocaine- and amphetamine-regulated transcript, were up-regulated. Fifty-two genes were selected for validation, and 12 transcriptional changes were confirmed. These results provided evidence that estradiol evokes broad transcriptional response in the cortex. Modulation of key components of the calcium signaling pathway, dopaminergic, serotonergic, and glutamatergic neurotransmission, may explain the influence of estrogens on cognitive function and behavior. Up-regulation of cocaine- and amphetamine-regulated transcript contributes to the neuroprotective effects of estradiol. Identification of estradiol-regulated genes in the frontal cortex helps to understand the pathomechanism of neurological and psychiatric disorders associated with altered levels of estrogens.