The aim of the research project is to characterize the physiology and pharmacology of excitatory amino acid (EAA)-mediated synaptic transmission in neostriatum. Neurochemical and electrophysiological evidence indicates that corticostriate synapses use glutamate or a similar EAA as their neurotransmitter. In addition, afferents from other brain regions (e.g. subthalamic nucleus) may also excite neostriatal neurons via EAA-mediated transmission. Since cortical afferents constitute a large source of excitatory input to neostriatal neurons, characterizing this EAA-mediated transmission is a key element in developing an understanding of striatal function. It is known that EAA-mediated transmission can be evoked by electrical stimulation in cortex or within the neostriatum itself. In addition, the presence of several types of EAA receptors has been demonstrated in neostriatal neurons. However, further work is needed to characterize the contribution of different receptors to synaptic responses, the effects of varying patterns of synaptic activation on synaptic efficacy and the role of EAA autoreceptors in modulating EAA-mediated transmission. Thus the hypotheses to be tested are: 1) That different patterns of activation of EAA-containing afferents making synapses onto striatal neurons are capable of producing not only excitatory transmission, but also plastic changes in transmission (e.g. use-dependent depression, posttetanic potentiation); 2) That multiple EAA receptors contribute to responses produced by release of endogenous neurotransmitter; and 3) That glutamate autoreceptors regulate glutamate release from synapses in the striatum. There is suggestive evidence that EAA-mediated excitotoxicity may contribute to neurodegenerative diseases involving the striatum, Huntington's Disease in particular. In addition, it is possible that pharmaceutical agents acting at EAA receptors could be used to modulate striatal function in persons suffering from such disorders. It is hoped that elucidation of the physiology and pharmacology of EAA-mediated transmission in striatum will contribute to new therapeutic approaches to these disorders.
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