L-glutamate is the most abundant excitatory neurotransmitter in the mammalian central nervous system. It plays a major role in behavioral processes such as learning and memory, and is a key component of the neuroendocrine mechanism that controls sexual maturation. Although ionotropic glutamate receptors have been studied extensively in the rodent brain, both at the molecular and pharmacological levels, the postnatal ontogeny of these receptors in humans is poorly understood. To help resolve this issue, the proposed studies will use sexually immature male and female rhesus macaques (Macaca mulatta) to test various hypotheses regarding: 1) the temporal expression of genes encoding different glutamate receptor subunits, 2) the neurotransmitter identity of neurons that show developmental plasticity in glutamate receptor gene expression, and 3) the influence of the changing sex steroid environment on the induction of these developmental receptor changes. The studies will involve a series of molecular and immunohistochemical approaches to characterize and quantify glutamate receptor gene expression at three key stages of postnatal development: 1) infantile, 2) juvenile, and 3) peripubertal, both with and without experimental manipulation of circulating estradiol and testosterone concentrations. Because macaques and humans show similar postnatal cognitive developments and similar developmental changes in their sex-steroid environment, the proposed studies are expected to yield new information about the ontogeny of ionotropic glutamate receptors in humans. Moreover, because the subunit composition of different glutamate receptors determines their affinity for different ligands (e.g., NMDA, AMPA and kainate) and influences their functional properties (e.g., permeability to Ca2+), elucidation of the mechanisms that regulate their developmental expression should help to lay a foundation for the development of pharmacological treatments for pediatric neurological disorders.
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