Temporal lobe epilepsy commonly becomes progressive and resistant to anticonvulsant drugs, and is often accompanied by cognitive and memory dysfunction. Experimental and human observations have established that hippocampal circuitry is reorganized by neuronal loss, gliosis, and axon sprouting in temporal lobe epilepsy, and that poorly controlled epilepsy can induce a continuing process of circuit reorganization potentially contributing to progressively intractable epilepsy and cognitive dysfunction. Despite substantial evidence for reorganization of hippocampal circuits by primary pathological insults or repeated seizures, it has been surprisingly difficult to detect functional abnormalities in the circuitry of the reorganized dentate gyrus in normal physiological conditions. The major goal of this proposal is to determine if functional abnormalities such as recurrent excitation and network synchronization emerge and progress in reorganized circuits as a result of activity-dependent alterations in the extracellular environment. The proposed experiments employ physiological, anatomical, and molecular techniques to systematically examine how interactions between reorganized circuitry and activity-dependent alterations in the extracellular environment promote emergent network properties such as recurrent excitation and epileptic synchronization. Because recurrent excitation is a critical processes contributing to seizure generation, and susceptibility to synchronization is the defining feature of epilepsy, the proposed experiments address issues that are important for understanding fundamental aspects of this common clinical disorder. Insights into how the extracellular environment influences emergent functional properties of reorganized neural circuits are pertinent to understanding both acute and chronic processes of epileptogenesis, and would potentially provide new perspectives and strategies for preventing seizures and the consequences of epilepsy.
