Most theories of nervous system function depend heavily ont he 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 which 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 of permanent changes that take place in memory formation and learning. Recently there are suggestions that similar long term changes take place as part of the mechanism of drug addiction and long term alterations in synaptic function may explain the symptoms of withdrawal experienced by addicts when drug administration is terminated. Glutamate receptors are known to be permeable to calcium ion which is thought to be the signal which is essential for initiating long-term potentiation and long term depression. Inappropriate activation of glutamate receptors is thought to contribute tot he 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. There is considerable evidence that over activation of glutamate receptors leads to a rise in free calcium ion inside the cell which can lead to nerve cell death. Thus understanding the regulation of calcium permeability may be crucial to understanding neurological disease and head injury as well as the basic mechanisms of memory acquisition and drug addiction. The cloning of the glutamate e receptors gene family led to the surprising discovery that all glutamate receptors are potentially permeable to calcium and this new realization is a major focus of this proposal. The AMPA glutamate receptors subtype mediates most excitatory synaptic transmission in the brain but little is known about the function of the kainate glutamate e receptor subtype which is the focus of this grant application. 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 by making mutations in mice using the homologous recombination and trans-gene technology. New methods will be developed to produce mutations in specific cell types in the brain in adult mice after development has occurred. Mutations will be made which knock out specific kainate receptor subunits or alter their calcium permeability. The mutant mice will be studied to determine the effects of mutation of the kainate receptors on synaptic transmission, transmitter release, synaptic plasticity, learning and drug addiction. Results from these studies will provide insight into the role that specific glutamate receptor subtypes play int he nervous system. This should make it possible by using recombinant DNA technology to develop new drugs and therapies to treat mental illness, degenerative diseases and drug addiction.
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