Elucidating the role of microglial group III metabotropic glutamate receptors in microglial inflammation : focus on Parkinson's disease and neuroprotection

Abstract

Microglia, the resident immune cells in the central nervous system, are implicated in the progressive neuronal death seen in Parkinson’s disease. Microglia are responsible for host defence by mounting an inflammatory response against pathogens and injury. However, if the inflammatory response is not controlled, collateral neuronal damage may occur, leading to neuronal degeneration. Microglia express metabotropic glutamate receptors (mGluR), and their activation has important effects on microglial inflammation. mGluR are a class of G-protein coupled receptors responsible for modulating glutamate transmission. They are divided into three main groups, according to their signalling mechanisms and sequence homology. However, activation of individual receptors within a single group can have varying consequences on microglial biology and microglia-driven neurotoxicity. Therefore, it is important to characterize the effects of each receptor on microglial inflammation if they are to be developed as a therapeutic target against neurodegenerative diseases. This thesis focuses on the effects of individual microglial group III mGluR on microglial inflammation in vitro. We have used an immortalized mouse microglial cell line whose inflammatory response to bacterial endotoxin and mGluR expression were validated by comparison with primary rat microglia. We have found that activating individual receptors within the group III mGluR has differing effects on microglial inflammation, either reducing or increasing various inflammation parameters. Importantly, these effects translated into either a neuroprotective or neurotoxic microglial phenotype against cultured dopaminergic neurons. Furthermore, the signalling mechanisms engaged by microglia group III mGluR were shown to differ from the canonical mGluR signalling mechanism most often found in neurons. This work therefore adds to the knowledge of group III metabotropic glutamate receptor biology and its potential as a therapeutic strategy against neurodegenerative diseases, highlighting the importance of differences between receptors putatively sharing signalling mechanisms.