Analysis & Control of Non-Synaptic Epileptiform Activity

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DESCRIPTION (provided by applicant): Epilepsy is characterized by the abnormal synchronization of large numbers of neurons. The synchronization and propagation of epileptic seizures are thought to rely on synaptic transmission. However, non-synaptic mechanisms such as neuronal swelling, electric field effects, potassium diffusion, gap junctions and glial cell function also contribute to the generation and spread of epileptiform activity. Non-synaptic epilepsy is generated by lowering calcium in the extracellular space thereby eliminating synaptic transmission. As a result, the clinical relevance of non-synaptic mechanisms has been questioned. We have recently generated novel models of non-synaptic activity in the presence of normal calcium and normal synaptic transmission. We propose to analyze the role of non-synaptic mechanisms in neuronal synchronization in order to understand and potentially develop novel therapies to prevent abnormal neural activity. We have recently shown that the frequency, amplitude and duration of non-synaptic epileptiform events can be controlled independently suggesting that different mechanisms are responsible. In particular, preliminary experiments show that gap junctions are not responsible for the propagation of non-synaptic events generated in zero-calcium medium, but that potassium diffusion (potentially mediated by the activity of glial cells) plays a crucial role. The goal of this proposal is to analyze and control non-synaptic epileptiform activity. Specifically, we propose to 1) determine the common mechanisms underlying three models of non-synaptic epilepsy, 2) establish the conditions sufficient for the generation of non-synaptic epileptogenesis, 3) analyze the mechanisms underlying the propagation of non-synaptic epileptiform activity, 4) develop a computer model of non-synaptic propagation to test hypotheses not directly testable by experimentation, and 5) develop methods for controlling epileptiform activity. Multi-disciplinary experimental approaches such as computer simulation and fluorescence imaging will be combined with pharmacology and in-vitro slice electrophysiology to achieve these goals. Current therapeutic agents are not capable of controlling seizure activity in 25 percent of all epileptic patients. The results of our studies should provide valuable insight into mechanisms underlying epileptogenesis as well as new tools for the control and suppression of epileptic seizures.