Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma

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DESCRIPTION (provided by applicant): The goal of this research is to understand why cerebral cortical trauma often leads to paroxysmal activity. Within 24 hours following head injury, up to 80% of patients with penetrating wounds display clinical seizures. Such acute seizures often initiate epileptogenesis the subthreshold processes that lead to spontaneous, recurring seizures and ultimately to epilepsy. We propose to study the electrophysiological features of trauma- induced epileptogenesis in chronic experiments in vivo, in vitro and with computational models that will be developed in close contact with the experiments. The primary hypothesis for the cause of epileptogenesis that we will test is that trauma-related chronic blockade of activity may activate homeostatic plasticity mechanisms that upregulate depolarizing influences (such as excitatory intrinsic and synaptic conductances) and downregulate hyperpolarizing ones (such as inhibitory conductances). Under the abnormal conditions found in traumatized cortex, this may create an unstable balance that leads to paroxysmal seizures. Multisite local field potential recordings (up to 64 channels) will be used to test the hypothesis that invasive brain trauma creates heterogeneous under- and overexcited cortical areas and that interaction of these areas increases the likelihood of seizure occurrence. Direct evidence for the role of homeostatic plasticity in the epileptogenesis will be obtained by measuring changes in minis, synaptic responsiveness, axonal arborization, intrinsic cellular properties, and multisite focal field potentials. Measurement will be performed over the medium-term (days) and long-term (weeks). In vivo electrophysiological semichronic and chronic experiments, in vitro experiments from chronically deafferented cortical slices as well as morphological studies will be performed at Laval University (Canada). Data from studying the conditions that increase the likelihood of seizure development after brain trauma will be studied using Independent Component Analysis (ICA) at the Salk Institute and will be incorporated into Hodgkin-Huxley type models of cortical neurons and networks at the UC Riverside. The goal of the computational models is to explore the interplay between all of the changes that occur in the cortex in vivo during epileptogenesis and to make predictions for interventions that could prevent seizures. The design of these interventions will be based on approaches that could be further developed to treat humans with trauma-induced epilepsy in clinical settings. PUBLIC HEALTH RELEVANCE: Within 24 hours up to 80% of patients with penetrating head wounds display clinical seizures. Following the Vietnam and Croatia wars, approximately 50% of patients with penetrating cranial wounds developed epilepsy characterized by recurring seizures 10-15 years later. Understanding and preventing epileptogenesis is a central problem in epilepsy research.