To examine the role of each metabotropic glutamate receptor (mGluR) subtype in physiology To examine the role of each mGluR subtype in selected neuropathological models . To develop selective agonists and antagonists of mGluRs.
Functional properties of neuronal populations expressing diverse mGluR subtypes will be studied by utilising electrophysiological, biochemical and anatomical techniques. The presynaptic mechanisms whereby mGluR subtypes control neurotransmitter release or the activity of ligand-gated or voltage-operated channels will be evaluated. Molecular biology studies with mGluR chimeras or transfected cells expressing mGluRs will identify critical domains responsible for their specific properties. Finally, attempts to correlate electrophysiological observations with behavioural tasks will also be performed.
Gene expression, pharmacology and electrophysiology of mGluRs will be studied in models of cerebral ischemia in vitro and in vivo and in epilepsy. Behavioural (motor and learning), electrophysiological and biochemical abnormalities will be evaluated in transgenic mice lacking specific mGluRs and in animals treated with antisense oligonucleotides directed against mGluR mRNAs or with selective mGluR subtype antagonists, when developed. We expect to clarify the role played by mGluRs in these pathologies, and whether their activation or blockade might become potentially useful in clinical practice.
Preliminary experiments indicate that aminoindane dicarboxylates (conformationally restricted analogues of phenylglycines) may selectively interact with mGluR subtypes with IC50S in the micromolar range. These compounds were synthesised and patented by three groups participating in this Project and they will be made available to other groups and tested. Since a higher degree of selectivity and affinity are still needed for mGluR research, in the course of this Project new molecules will be designed, synthesised and studied. Upon completion of the Project, novel pharmacological tools will be made available to the scientific community, as well as molecules which might be developed as drugs.
Funding SchemeCSC - Cost-sharing contracts
3584 CG Utrecht
BS8 1TD Bristol
DD1 9SY Dundee