Estrogen receptor gene activity within the brain and the relation to psychiatric disorders : mapping and function

Estrogens have for a long time been known to regulate neuroendocrine functions in the central nervous system (CNS), primarily related to reproduction. In recent years estrogens have been found to also modulate many other brain functions, for example mood and cognition. Gonadal hormones appear to influence the expression of several neuropsychiatric diseases, such as affective disorders, schizophrenia, and Alzheimer's disease. Estrogen receptors (ERs) mediate several of the estrogenic effects and to date two different ER subtypes are known, the ER[alpha] and ERß. Very limited information was available regarding the ER neuronal populations in the human brain.

The anatomical distribution of the ER[alpha] and ERß mRNA expression was investigated (using in situ hybridization histochemistry) in both rodent and human post mortem brain tissue to address the question of the potential different functional CNS roles of the two ER subtypes and to determine possible species differences in the ER neuronal system. Distinct expression patterns were evident for the two ER mRNA subtypes, though both were expressed predominantly in limbic-related structures (e.g., amygdala, hypothalamus, and hippocampus), suggesting that the two ERs might mediate different functions in the CNS. In humans, the ER[alpha] mRNA dominates in the amygdala and hypothalamus, suggesting a main role of the ER[alpha] in estrogen modulation of neuroendocrine and autonomic functions as well as emotions. In contrast, the ERß mRNA subtype was predominantly expressed in areas related to memory and learning, such as the hippocampal formation and entorhinal cortex. In general, the ER mRNA expression patterns were in good agreement between the species, although some differences (notable in the supra optic nucleus and the medial amygdala) were observed that should be taken in consideration when results from rodents are extrapolated to humans.

In addition to the discrete neuroanatomical patterns of the ER[alpha] and ERß mRNA distribution, the regulation of the ER expression was also assessed. The expression of the ER[alpha] and ERß mRNA were observed to be differently regulated by its hormone, 17ß-estradiol, in different brain regions, further supporting the hypothesis of distinct CNS roles of the two ER subtypes. The human ER[alpha] gene has been shown to be expressed from different promoters in a cell and tissue specific manner. The current data shows that the ER[alpha] gene expression is regulated by alternative promoters in different neuronal populations of the human brain. Thus, multiple promoter usage is a possible mechanism to achieve differentiated regulation of the neuronal ER[alpha] expression, dependent on the cell phenotype.

Estrogen treatment in female rats was shown to modulate the serotonin ER system, An imbalance of the 5-HT neurotransmitter system is implied in the pathophysiology of, primarily, affective disorders, but also of schizophrenia. Both acute and chronic 17ß-estradiol treatment of female ER rats were found to reduce the 5-HT1A receptor expression in several ER related brain areas. In a genetic animal model of depression, the ER sensitive rat line, alterations were observed within the 5-HT system (primarily lower 5-HT2A receptor mRNA levels). Interestingly, many of these abnormalities were found to be reversed by 17ß-estradiol treatment. The present findings suggest that the regulation by estrogens of the 5-HT2A, and possibly also the 5-HT1A receptor, might be an underlying mechanism in the hypothesized influence of gonadal hormones in the expression of affective disorders.

List of scientific papers

I. Österlund M, Kuiper GG, Gustafsson JA, Hurd YL (1998). Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain. Brain Res Mol Brain Res. 54(1): 175-180.
https://pubmed.ncbi.nlm.nih.gov/98202851

II. Österlund MK, Keller E, Hurd YL (1970). The human forebrain has discrete estrogen receptor alpha mRNA expression: high levels in the amygdaloid complex. Neuroscience. [Accepted]

III. Österlund MK, Warner M, Gustafsson JÅ, Hurd YL (1970). Estrogen receptor beta mRNA expression within the human forebrain: distinct distribution pattern to the ERalpha. [Submitted]

IV. Österlund MK, Grandien K, Hurd YL (1970). The human brain has distinct regional distribution patterns of alternative estrogen receptor alpha gene promoter activity. [Submitted]

V. Österlund MK, Hurd YL (1998). Acute 17 beta-estradiol treatment down-regulates serotonin 5HT1A receptor mRNA expression in the limbic system of female rats. Brain Res Mol Brain Res. 55(1): 169-172.
https://pubmed.ncbi.nlm.nih.gov/98309940

VI. Österlund MK, Halldin C, Hurd YL (1970). Effects of chronic 17-estradiol treatment on the serotonin 5-HT1A receptor mRNA and binding levels in the rat brain. Synapse. [Accepted]

VII. Österlund MK, Overstreet DH, Hurd YL (1970). The Flinder Sensitive Line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17beta-estradiol. Mol Brain Res. [Accepted]