Translational studies of group II metabotropic glutamate receptors (mGluR2, mGluR3) and their role in schizophrenia

All current drugs used to treat schizophrenia work by blocking actions of a brain chemical transmitter called dopamine. Unfortunately these drugs are not very effective and have many side-effects. Recent research has suggested that another transmitter, glutamate, is also important in schizophrenia, and that drugs working on this system may be better. Glutamate acts by binding to molecules called receptors. One subtype of these is called group II metabotropic glutamate receptors (mGluRs), and these are of great interest because last year a drug which acts on these receptors was shown to be effective (and free of major side effects) in treatment of schizophrenia - the first ever non-dopamine drug to succeed in the illness. We have been working on group II mGluRs for several years, and this application seeks to build upon our existing knowledge and expertise to disover more about how these receptors work and so help make better drugs for schizophrenia. To do this, we will use genetic and molecular methods, investigate how brain cells work in the absence of these receptors, and study the receptors in the brains of people who had the illness. In line with this funding scheme, the work will be done jointly and in active collaboration with colleagues at GlaxoSmithKline in Harlow.

Group II metabotropic glutamate receptors (mGluRs) contribute to the regulation of glutamate transmission, particularly via their role as inhibitory autoreceptors. They have been implicaetd in schizophrenia, especially its cognitive dysfunction, based upon genetic and pharmacological studies. Now, striking recent evidence has emerged that group II mGluR agonists may be effective, tolerable non-dopaminergic antipsychotics. This project will investigate several important aspects of the neurobiology of these receptors in normal brain and in schizophrenia. It takes advantage of our existing work on mice in which one or both receptors has been deleted, and on the molecular biology of the receptors, which together give us a unique competitive advantage in this exciting field. Our work to date shows, amongst other findings, that group II mGluR-deficient mice are impaired in working memory and synaptic plasticity. Our human studies have identified the first splice variants of group II mGluRs, and indicate that they may be functionally important. Four main sets of experiments are planned here. All will be conducted collaboratively with GSK at Harlow, with whom we have already worked on mGluRs for several years. (1) Glutamate transmission will be determined directly in group II mGluR-deficient mice, using in vivo and slice microdialysis, and electrophysiology, at baseline and after stimulation by phencyclidine (PCP, a widely used agent in schizophrenia rodent models). (2) We will characterise further the memory deficits of the mice, whether they are exacerbated by PCP, and whether they can be reversed pharmacologically with a range of ligands. (3) We will carry out microarray studies of the mice to identify the molecular profile resulting from loss of one or both group II mGluRs. (4) We will study group II mGluR expression in post mortem brains, to follow up reports of altered receptor dimerisation, or splice variant expression. The work will in total provide substantial new information about group II mGluRs, directly relevant to their candidacy as targets of drugs for schizophrenia and other disorders in which they are implicated. Our work will also dissect out clearly the differential roles of mGluR2 and mGluR3, which will also be of value in future drug discovery efforts.