Avi Nisim: Introduction: Many human diseases such as stroke, epillepsy, and Alzheimer's disease are suspected to occur due in part to glutatmate associated excitotoxicity. Glutamate is the major excitatory neurotransmitter in the brain. Pyramidal cells within the hippocampus are rich in receptors which bind glutamate. Such receptors can be classified under two general classes NMDA and non-NMDA. Upon binding of glutamate to the NMDA receptor, calcium is able to enter the cell and play a key role in long term potentiation of the cell. It is also suspected that non-NMDA receptors allow limited amounts of calcium to enter the cell as well. There exists an interesting relationship between NMDA and non-NMDA receptors. Specifically, at rest, magnesium ions are anchored onto the NMDA receptors thus preventing the flux of calcium regardless of the receptor's ability to bind to glutamte. The ability to remove magnesium from the NMDA receptors is a voltage dependent event which relies on a quantized amount of non-NMDA receptors opening and thus altering the cell's potential. The Problem: Although calcium plays a critical role in many physiological events, at high concentrations it can alter normal cellular function and even cause cell death. Glutamate excitotoxicity occurs due excess intracellular influx of calcium. Although the exact mechanism by which cell death occurs is still under investigation, several potential models such as apoptosis, and necrosis have been suggested. Once the onset of cellular degeneration occurs, a domino effect takes place and severe neurodegeneration is observed. Project Aims: In this project I utilize a pharmacological approach to study role which non-NMDA receptors play in this type of Neurodegeneration. That is, GYKI-52466 as well as CNQX are non-NMDA antagonists. That is, these drugs prevent the non-NMDA receptors from opening in the presence of glutamate. Animal Model: Traditionally, excitotoxicity has been studied with animal models in which lesions to the brain are induced via electrical kindling, or injections with kainate acid. We are fortunate in this laboratory to be able to work with a mutant starin of Han Wistar rats which displays a naturally occuring autonomic recessive mutation which is manifested by progressive neurodegeneration culminating in the animal's death at approximately 60 days of age. Previous studies suggest that the observed neurodegeneration in this mutant occurs due to glutamate excitotoxicity. Therefore, we have the unique opportunity to be able to study the mechanism associated with this degeneration in an intact animal. Working hypothesis: The following two considerations are of primary importance at arriving at my hypothesis: 1. The unique relationship which exists between NMDA and non-NMDA receptors. 2. The ability of calcium to enter through non-NMDA receptors (specifically, GluR2). It is for the above briefly described considerations that I suspect that non-NMDA play both a direct and an indirect role in the manifested neurodegeneration. Treatment: I utilize a pharmacological approach to implicate the role which the non-NMDA receptors play in the observed neurodegeneration. Animals are treated with various non-NMDA antagonists (GYKI-52466, CNQX) for three weeks strating at 30 days post natally (30 days is chosen due to the fact that at this age earliest confirmations of the mutation can be determined--this does not represent the clinical onset of the Sx, but the earliest time which we can confirm the presence of the mutation by visual examination (hyperactivity, and shaking) In the future, I will include some of the perliminary findings in this site. I am looking forward to attending this year's neuroscience meeting which is held in November at Washington D.C., where I will be presenting a poster of my findings. If you wish to e-mail me please don't hesitate; aan20682@csun.edu