The role of group I metabotropic glutamate receptors (mGluR1? and mGluR5) in glutamate-induced neuronal excitotoxicity in Alzheimer's disease

Metabotropic glutamate receptors (mGluRs) have become a pharmacological target for neuroprotective drug development. MGluRs are 7-transmembrane-domain proteins that couple to G-protein and are involved in controlling second messenger levels. Since glutamate play a crucial role in neurotoxicity of Alzheimer’s disease (AD), mGluRs may represent a pharmacological path for producing a relatively subtle modulation of glutamate systems in the CNS. Aims of the study were: 1) determine regional mGluR1α and mGluR5 levels in healthy human controls and AD cases; 2)search for potential ligands for group I mGluRs. Immunohistochemistry, performed using mGluR1α and mGluR5 polyclonal antibodies on paraformaldehyde-fixed tissue sections, showed that mGluR1α immunoreactivity was concentrated in the stratum lucidum and molecular layer of dentate gyrus in both control and AD hippocampus, whereas abundant mGluR5 immunoreactivity was found in pyramidal cells and the pleomorphic cell layer of the dentate gyrus in AD hippocampus cf. weak labeling in controls. No mGluR1α immunoreactivity was found in either control or AD occipital cortex. Strong mGluR5 signals were detected in control occipital cortex. Predominant mGluR5 staining was observed in AD mid-temporal cortex. Western-blot and [3H]quisqualate binding assays were also used to define the mGluR1α and mGluR5 receptor profiles. It showed that mGluR5 was expressed prominently in hippocampus. A radioligand binding assay was used to screen venoms extracted from Conus snails as potential ligands