Hormonal Modulation of Amino Acid Neurotransmitter Metabolism in the Arcuate Nucleus of the Adult Female Rat: A Novel Action of Estradiol

Morphological plasticity in response to estradiol is a hallmark of astrocytes in the arcuate nucleus. The functional consequences of these morphological changes have remained relatively unexplored. Here we report that in the arcuate nucleus estradiol significantly increased the protein levels of the two enzymes in the glutamate-glutamine cycle, glutamine synthetase and glutaminase. We further demonstrate that these estradiol-mediated changes in the enzyme protein levels may underlie functional changes in neurotransmitter availability as: 1) total glutamate concentration in the arcuate nucleus was significantly increased and 2) microdialysis revealed a significant increase in extracellular glutamate levels after a synaptic challenge in the presence of estradiol. These data implicate the glutamate-glutamine cycle in the generation and/or maintenance of glutamate and suggest that the difference in extracellular glutamate between estradiol- and oil-treated animals may be related to an increased efficiency of the cycle enzymes. In vivo enzyme activity assays revealed that the estradiol mediated increase in glutamate-glutamine cycle enzymes in the arcuate nucleus led to an increase in gamma-aminobutyric acid and is likely not related to the increase in extracellular glutamate. Thus, we have observed two-independent effects of estradiol on amino acid neurotransmission in the arcuate nucleus. These data suggest a possible functional consequence of the well-established changes in glial morphology that occur in the arcuate nucleus in the presence of estradiol and suggest the importance of neuronal-glial cooperation in the regulation of hypothalamic functions such as food intake and body weight. (Endocrinology 150: 3237-3244, 2009)