This proposal addresses the functional development of glutamate receptors (GluRs) in the neostriatum (NS), concentrating on the N-methyl-d-aspartate (NMDA) receptor. NMDA receptors are considered one of the most important subtypes of GluRs and there is considerable evidence that nervous system development is critically dependent upon NMDA receptor function. Understanding developmental regulation of NMDA receptors is particularly important in the NS where control of motor programs and cognitive abilities are determined. The main driving force behind NS activation and the most important transmitter system in the NS is the Glu-containing system that originates from the cortex. This system makes monosynaptic contacts with all subtypes of NS cells, has a primary role in NS information processing, is implicated in use-dependent plasticity and during early developmental periods may have trophic influences. If Glu inputs and receptors are the prime activators of adult NS cells, the development of GluRs can be expected to have major implications for NS functioning during postnatal maturation. Experiments are designed to examine when GluRs become functional and when Glu-containing synapses make functional contacts on two subpopulations of NS cells, medium- and large-size cells. One hypothesis forms a framework for this proposal. It states that there are two age periods when NMDA receptor function in the NS will be particularly important, an early period [from postnatal days (PNDs) 7-14] as asymmetrical synapses are forming, and a later period (PNDs 20-22) at the end of the peak period of formation of corticostriatal synapses. To test this hypothesis, NMDA receptor development will be compared with that of (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate (KA) receptors in the two subpopulations of NS neurons. State-of-the-art electrophysiological methods in which cells in slices are visualized before and during whole cell clamp recordings will be used to assess the developmental alterations in GluR agonist-evoked currents. Mechanisms by which NMDA receptor function changes developmentally will be examined. These include development of voltage-dependence, development of receptor binding, development of mRNA and protein expression for GluR subunits, and development of modulation of NMDA receptor function by metabotropic GluRs, dopamine and protein kinases. In combination, complementary information will be integrated to provide a complete picture of the development of NS GluRs. The outcomes will provide information necessary to understand the role of these receptors in NS development and provide clues for generating rational strategies to treat GluR dysfunction during development and in the adult.
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