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Mechanism Underlying Estrogen Attenuation of Neuronal Injury
Brigitte J. Todd
School of Medicine, University of Maryland, Baltimore

Estradiol, the major gonadal sex steroid hormone in females, is an important regulator of gene transcription throughout development and in the adult. Numerous studies have shown that estradiol acts as a neuroprotective agent, and also as a trophic factor in the developing and adult brain. During development, estradiol acts to prevent apoptosis in specific regions of the brain, resulting in sexually dimorphic brain regions in females and males. Moreover, estradiol has been shown to reduce the magnitude of cell death in a variety of neuronal injury models. Clinically, estradiol may attenuate effects of some neurodegenerative diseases. Understanding the mechanisms by which estradiol acts to promote neuronal growth and protection remains a major goal of neuroscience and women's health.

The amino acid GABA is the major inhibitory neurotransmitter in the adult brain, and is particularly prevalent in the hypothalamus, where over half of all nerve terminals are GABAergic. Despite this well characterized role as an inhibitory transmitter in the adult however, GABA actually acts as an excitatory transmitter in the developing brain, depolarizing neurons sufficiently to open voltage-gated calcium channels and cause calcium influx. This property of GABA allows it to act as a trophic factor in the perinatal brain, influencing neuronal survival, neurite outgrowth and synaptogenesis. Importantly, GABA can have excitatory actions in adult neurons as well: after neuronal trauma, GABA switches back from inhibitory to excitatory. The reason for this switch is unknown, but it is possible that by reverting to its perinatal phenotype, the cell can once again use GABA to elevate intracellular calcium, thus affecting neuronal growth and survival.

We have previously shown in prenatal hypothalamic cell cultures that estradiol increases the magnitude of GABA responses, and delays in developmental switch from excitatory to inhibitory. This observation has led to the current hypothesis that estradiol attenuates cell death in neuronal injury by promoting the action of excitatory GABA. Specific aims are to:

characterize intracellular calcium responses to GABA_A receptor activation following injury, with and without the presence of estradiol.
investigate whether cells that respond to GABA as excitatory have steroid receptors, or if the steroid action is indirect.

All experiments will be carried out in mixed neuronly-astrocyte cultures derived from embryonic hypothalamus, and grown for up to 30 days, until GABA responses are inhibitory. Neuronal injury will be induced by scraping cells from coverslips and replating. Cell responses to GABA will be ascertained by intracellular calcium imaging. Presence of estrogen receptors will be determined by immunocytochemistry.