The trafficking and anchoring of neurotransmitter receptors to the neuronal plasma membrane are complex phenomena that involve specific interactions between the receptors and various scaffolding proteins. Over the past few years, the targeting of metabotropic glutamate receptors (mGluRs) has gained particular interest. The group I mGluRs, which comprises mGluR1 and mGluR5, are mostly expressed postsynaptically and produce slow depolarization through coupling with phospholipase C and IP3/Ca2+ receptors. Five years ago, Brakeman et al. (1997) identified a dendritic protein that selectively binds to group I mGluRs. The expression of this protein, which was named HOMER, appeared to be regulated by physiological synaptic activity and likely played a role in group I mGluRs signaling. Since then, 12 Homer cDNAs have been cloned. These cDNAs encode for various proteins with a similar structure named Homer 1a/b/c, Homer 2a/b and Homer 3. Although the exact functions of Homer in the brain remain to be established, various data, largely obtained in cultured cells, suggest that Homer is involved in the trafficking and synaptic targeting of group I mGluRs at specific sites along the neuronal plasma membrane. There is strong evidence that changes in dopamine transmission regulate Homer mRNA expression in the rat CNS. The lack of information on Homer proteins localization and their relationships with group I mGluRs hampers the progress of knowledge on Homer/mGluRs functional interactions in the CNS. During the first five years of this award, our laboratory studied in detail the subsynaptic and subcellular localization of group I mGluRs in the monkey basal ganglia. Two major findings stood out from these studies: (1) Group I mGluRs are expressed at both glutamatergic and non-glutamatergic synapses in various basal ganglia nuclei and (2) a large pool of mGluR5 is expressed intracellularly in basal ganglia output nuclei. These observations raised important questions regarding the functions, synaptic targeting, trafficking and regulation of group I mGluRs in the basal ganglia. In order to further characterize these issues and better understand the potential role(s) of Homer in basal ganglia functions, one of the objectives of this proposal is to elucidate the subcellular and subsynaptic relationships between Homer and group I mGluRs in the striatopallidal complex of monkeys. Another goal of this project is to characterize potential changes in the subcellular and subsynaptic localization of group I mGluRs in normal versus Homer knock out mice with or without lesion of midbrain dopaminergic neurons. Together, findings obtained in these studies will serve as a basic framework to understand Homer/mGluRs interactions in normal and pathological basal ganglia functions.
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