Explore the Mechanism of Hypothalamus Glutamate Synaptic Plasticity on the Regulation of Sexual Differentiation during Neonatal Critical Period

The expressions of normal sexual behavior ensure the capability of continually species propagations. The males and females express different sexual behaviors. In rats, for example, the males express mounting behavior, while the females express lordosis behavior. The mechanism for the expression of male mounting behavior is due to estradiol (E2) aromatized from testosterone increases the releases of glutamate (Glu) from astrocytes in pre-optic area and from neurons in hypothalamus, which respectively cause the brain musculinization and de-feminization during the critical period. In contrast, due to absence of E2 exposure, the female brain is feminized during the critical period, which induces the expression of lordosis behavior. However, the mechanism of Glu synaptic plasticity for the regulation of the sexual 2 differentiation is still obscure. On the other hand, the glutamate-glutamine cycle (GGC) between astrocytes and neurons regulates synaptic efficacy of glutamatergic neurons in hippocampus. Moreover, E2 increases the protein expressions of glutamine synthetase (GS) and glutaminase, two key enzymes involved in GGC. The central hypothesis of this proposal was that due to the males have higher concentration of E2 than the females in the hypothalamus, the glutamate synaptic transmission of the males is GGC-independent, which contributes to the arrangements of de-feminized brain phenotype of glutamatergic synapses; while that of the females is GGC-dependent, which causes the formation of feminized brain phenotype of glutamatergic synapses during the critical period, and these, in turn, determine the expressions of sexually dimorphic reproductive behaviors during adulthood. Combining the techniques of pharmacology, reproductive behavior observations, electrophysiological recordings with western blot analysis, we listed three specific aims for the proposal: 1) To determine that the normal function of GGC is necessary for the expression of normal reproductive behavior of the females during the critical period. 2) To elucidate that the female glutamate synapses are GGC-dependent, while that of the males are GGC-independent, during the critical period. 3) To demonstrate that during the critical period, blockade of the male E2 receptors switches the glutamate synapses into GGC-dependent feminized synapses and reduces expression of mounting behavior during adulthood; in contrast, administrations of E2 to the females alter that into GGC-independent de-feminized synapses and decrease expression of lordosis behavior during adulthood. The study of the mechanism of sexual differentiation mediated by interactions between glutamate synaptic plasticity and GGC may provide a novel clue for pharmaceutical companies to develop drugs for the treatments of sexual dysfunctions induced by GGC malfunction.

Project ID:PC10607-0343
External Project ID:MOST106-2320-B182-010