Hormonal modulation of neuronal-glial interactions in the arcuate nucleus of the adult female rat

Abstract

Morphological plasticity in response to estradiol is a hallmark of astrocytes in the arcuate nucleus, with estradiol causing an increase in astrocytic surface area. The increase in surface area correlates with changes in synaptic patterns in both the developing and adult brain. The functional consequences of these morphological changes have remained relatively unexplored. The data presented here demonstrate a novel role for estradiol in modulating neuronal-glial interactions in the arcuate nucleus and its implications in the regulation of feeding behavior. Estradiol is a potent inhibitor of food intake, but the mechanisms of this phenomenon are largely unknown; however, it is clear that the arcuate nucleus is a key feeding nuclei and amino acid neurotransmission may be important. The glutamate-glutamine cycle is a classic example of a neuronal-glial cooperation, which is essential to the maintenance of synaptic transmission. We have shown that in the arcuate nucleus estradiol increased the protein levels of the two enzymes in the glutamate-glutamine cycle, glutamine synthetase (GS) and glutaminase. These changes in enzyme protein were thought to underlie functional changes in neurotransmitter availability as (1) total glutamate concentration in the arcuate nucleus is significantly increased and (2) microdialysis revealed a significant increase in extracellular glutamate levels following a synaptic challenge in the presence of estradiol. However, in vivo enzyme activity assays demonstrated that the estradiol mediated increase in glutamate-glutamine cycle enzymes in the arcuate nucleus led to an increase in GABA production and is likely not related to the increase in extracellular glutamate. Therefore, we have observed two independent effects of estradiol on amino acid neurotransmission in the arcuate nucleus, which we hypothesized to be involved in the regulation of food intake. To test this hypothesis we measured the food intake of ovariectomized adult female rats treated with estradiol or oil vehicle and either saline or MSO, a specific inhibitor of GS activity. Inhibition of GS activity accelerated and prolonged the well-established estradiol-mediated decrease in food intake, demonstrating a role for neuronal-glial cooperation in the regulation of hypothalamic function.