Most theories of nervous system function depend heavily on the properties of the synapse and for this reason the synapse has been a focus of neuroscience research for many decades. The synapse is also the focus of medical and pharmaceutical research because in general the drugs that have proven useful for the treatment of mental illness and neurological disease act on various aspects of synaptic function, i.e. transmitter uptake and metabolism, ion channels and receptors. It is also likely that synaptic changes underlie the long term or permanent changes that take place in memory formation and learning. Recently there are suggestions that similar long term changes in synaptic transmission take place as part of the mechanism of many neurological diseases such as epilepsy, drug addiction and long term intractable pain. Long term alterations in synaptic function may explain the symptoms of withdrawal experienced by addicts when drug administration is terminated. Inappropriate activation of glutamate receptors is thought to contribute to the nerve cell death which occurs after brain injury due to stroke, epilepsy, head trauma and perhaps other neurological diseases such as ALS, Parkinson's and Alzheimer's disease. Little is known about the function of the kainate glutamate receptor subtype which is a major focus of this grant application made possible by the recent cloning of the kainate receptor genes. The structure of the glutamate binding site will be studied. A search for glutamate receptor modulatory and accessory proteins will be undertaken using a new molecular genetic approach. The calcium permeability and function of the glutamate receptors are regulated by a novel mechanism of RNA editing which will be studied and altered in mutant mice. The role of kainate receptors will be studied making use of a battery of mutant mice that we have engineered to alter the kainate receptor system and synaptic transmission. Results from these studies will provide insight into the role that specific glutamate receptor subtypes play in the nervous system. This should make it possible by using recombinant DNA technology to develop new drugs and therapies to treat epilepsy, pain, stroke, mental illness, degenerative diseases and drug addiction.
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