Our overall aim is to understand the molecular events that underlie glutamate receptor mediated signal transduction in the brain. In particular, we have studied the effect of glutamate receptor activation on the concentration of neuronal Ca, (Ca)i, and resulting effects on the state of neuronal mitochondria and the production of superoxide and other reactive oxygen species (ROS). In the present proposal we shall be interested in understanding how these events may be involved in glutamate receptor mediated excitotoxic neuronal degeneration, a process that is believed to be extremely important in many types of neurodegenerative diseases including stroke and epilepsy. We shall use imaging procedures to examine how the activation of glutamate receptors in the brain can regulate the state of mitochondria and the production of ROS and how these processes are regulated. We shall also be interested in how these processes can be altered by activation of the metabotropic glutamate receptors that are also stimulated by synaptically released glutamate. We shall further investigate the importance of Ca and ROS by manipulating the concentrations of key neuronal proteins such as superoxide dismutase and nitric oxide synthase using an adenovirus expression system. Overall we hope that these studies will increase our understanding of glutamate mediated signal transduction in the brain and its role in neurodegenerative disease.
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