Metabotropic glutamate receptors in the basal ganglia.

Recent advances in the molecular biology of glutamate receptors have identified a family of mGluRs with diverse second messenger effects and pharmacological properties. At the same time, mGluRs have become increasingly important in understanding basal ganglia functions because of the physiological actions attributed to them. The distribution of mGluRs in specific nuclei and cell populations of the basal ganglia is of direct relevance to clearly defining functional roles of individual mGluRs in the extrapyramidal system. An isotopic in situ hybridization protocol was designed for highly specific detection of closely related receptor family transcripts and used to examine the distribution of five distinct mGluR mRNAs in the adult male rat basal ganglia and related structures. Striking differences in mGluR mRNA expression profiles in basal ganglia were observed. MGluR1 is the only mGluR expressed in the substantia nigra pars compacta. The subthalamic nucleus is the only basal ganglia structure which expresses mGluR2, with the exception of rare striatal cells. The mGluR2-expressing striatal cells are probably cholinergic interneurons. MGluR5 was also differentially expressed within the striatum; 75-80% of striatal neurons were strongly labeled, but 20-25% exhibited low or no signal for mGluR5 mRNA. A double label in situ hybridization procedure was developed to investigate differential mGluR expression in neurochemically defined striatal neuron populations. MGluR5 was found to be strongly expressed in enkephalin projection neurons but very low or absent in cholinergic and somatostatin interneurons. This result implicates mGluR5 in indirect basal ganglia pathway control and vulnerability of projection neurons to excitotoxicity. Finally, agonists specific for different mGluRs were used as competitors of $\rm\lbrack\sp3H\rbrack glutamate$ metabotropic-like binding on brain sections. The rigid 2-(carboxycyclopropyl)glycine derivatives DCG-IV and scL-CCG-II are able to differentiate between two metabotropic binding site types. scL-CCG-II-sensitive binding sites are pharmacologically similar to group 1 mGluRs and found in regions where mGluR1 and mGluR5 are abundantly expressed. In contrast, high affinity DCG-IV sites may represent binding to group 2 mGluRs (mGluR2/3). Quantitative assays using these compounds are therefore well suited for measuring metabotropic binding in disease or experimental paradigms.PhDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105036/1/9624744.pdfDescription of 9624744.pdf : Restricted to UM users only