METABOTROPIC RECEPTORS AND EXCITOTOXICITY

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Glutamate receptors (GluR's) mediate the majority of excitatory signal transduction within the mammalian central nervous system. Excitotoxicity, a process in which abnormal activation of GluR's leads to neuronal death, is thought to play a role in numerous neurological conditions. The role of GluR's linked to ion channels ("ionotropic" glutamate receptors, iGluR's) in excitotoxicity has been well documented. Activation of GluR's linked to second messenger systems ("metabotropic" glutamate receptors, mGluR's) can also influence excitotoxicity. mGluR's which stimulate phosphoinositide metabolism may exacerbate excitotoxicity, whereas those mGluR's which inhibit cyclic AMP production may attenuate excitotoxicity. While the mechanisms by which mGluR's influence excitotoxicity remain unclear, one possibility is that mGluR's influence excitotoxic processes by altering the function of iGluR's, for example, through phosphorylation of iGluR's. mGluR's thus offer an attractive potential target for the development of therapeutic neuroprotective agents. The objective of this proposal will be to determine how mGluR's affect iGluR-mediated striatal excitotoxicity. Three main areas will be investigated: 1) the ability of mGluR agonists and antagonists as well as of antisense oligonucleotides directed against specific mGluR's to influence in vivo excitotoxicity, 2) the ability of antagonists, activators, and antisense oligonucleotides targeted against mGluR-linked second messenger systems to influence in vivo excitotoxicity, and 3) the effect of mGluR receptor stimulation on iGluR phosphorylation. The determination of in vivo excitotoxicity will involve lesion size analysis in a well characterized model: stereotaxic intrastriatal injection in the rat. In addition, reverse transcription-PCR, in situ hybridization, receptor binding, Western blotting, striatal cell culture, and functional biochemical assays will be employed to assess both the efficacy of anti sense oligonucleotide treatment, as well as regulation of receptor function. Taken together, these studies are designed to shed light on the important interactions between different types of GluR's, especially as they pertain to excitotoxicity. Once the relationships have been elucidated, mGluR's themselves may become logical targets for the development of novel neuroprotective agents.