Epilepsy affects 2-5% of people and is often associated with long-term neurological deficits, such as learning disabilities and cerebral palsy. Although seizures may directly cause neuronal death in some clinical contexts, in other situations seizures do not appear to induce neuronal death, but may still have detrimental effects on neuronal structure and function. While seizure-induced neuronal death via excitotoxicity and apoptosis has been studied extensively, mechanisms of non-lethal neuronal injury from seizures are poorly understood. Recently, dendritic spines of neurons have been found to exhibit rapid motility in response to various physiological stimuli, suggesting a role of spine motility in important neuronal functions, such as learning. As seizures involve excessive neurophysiological activity, the major hypothesis of this research proposal is that seizures induce direct, rapid changes in dendritic spines, which vary depending on specific seizure properties. The main objective of this proposal is to investigate the rapid effects of seizures on dendritic spine density, morphology and motility in animal seizure models, utilizing advanced cellular imaging techniques, such as confocal microscopy, two-photon imaging, and transgenic mice expressing green-fluorescent protein. The time course and effect of kainate and pentylenetetrazole-induced in vivo seizures on dendrites will be examined in fixed brain sections. Real-time changes in dendritic structure and motility will be analyzed during pharmacologically induced electrographic seizures in intact anesthetized animals in vivo. Cellular mechanisms mediating rapid seizure-induced spine changes will be investigated in live brain slices in vitro. The principal investigator (PI) is an academic physician-scientist trained in both clinical epilepsy and basic epilepsy research. Although the PI has substantial experience in cellular and systems physiology related to animal seizure models, the added dimension of high-resolution cellular imaging supported by this Research Career Award (K02) should provide important insights into mechanisms of non-lethal neuronal injury from seizures and significantly aid the PI in developing an independent research career in epilepsy. Washington University possesses unmatched resources in cutting-edge technology and expert researchers in cellular imaging and represents an ideal environment for the PI to complete the goals of this proposal.
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