The goal of this project is to investigate the electrophysiological and neurochemical correlates of hippocampal neuronal pathology found in temporal lobe epilepsy. Hypotheses on neuronal excitability, neuronal inhibition and disinhibition, and synchronization of neurons will be tested during: l) the interictal period, 2) the transition to ictus, 3) the propagation of ictal activity and 4) the termination of ictal activity. Bilateral neurophysiological measures of these epileptic phenomena include I) the pattern of single neuron firing, 2) degree and extent of neuronal synchronization, 3) frequency and extent of epileptiform spikes and sharp waves, and 4) level of paired pulse excitability. Simultaneously, bilateral in vivo microdialysis measures of neurotransmitters will be sampled from the extracellular space immediately adjacent to the microelectrodes to look for differences between the hippocampal area of seizure onset and the contralateral homotopic area. Microdialysis measures will include the excitatory amino acid neurotransmitters glutamate and aspartate, the inhibitory neurotransmitter gamma-aminobutyric acid, and the opioid peptide neuromodulators, met- /leu-enkephalin, and dynorphin. The four hypotheses to be tested are: 1) During the interictal state, the epileptogenic hippocampus in human mesial temporal lobe epilepsy will display significantly enhanced inhibition and significantly enhanced excitation, as compared to homotopic hippocampal areas of the contralateral temporal lobe. 2) Two distinct mechanisms of transition to ictus occur, one disinhibitory due to decreased inhibition and increased excitation (Type A), the other hypersynchronous, requiring both increased inhibition and increased excitation (Type B). 3) Transition from a Type B ictal pattern to a Type A ictal pattern requires propagation to adjacent structures with different anatomical and physiological properties, prior to subsequent modifications in the electrophysiological patterns of activity of the structures initiating the seizure. 4) Cessation of Type A ictal events are associated with release of opioid peptides, which suppress unit discharges, while Type B ictal events do not release opioid peptides and seizures terminate as the involved neuronal aggregates become desynchronized. Results of these tests will be correlated with molecular pathophysiology measures of reorganization of excitatory and inhibitory hippocampal circuitry from Subproject #1, with Ca2+ signalling properties of glial cells in Subproject #2, and with in vitro measures of dentate gyrus extracellular negativity in Subproject #3. Knowledge of the physiology of the neuronal circuitry underlying interictal excitability, ictal onset and termination and propagation of ictal discharges in vivo in the intact human temporal lobe provides unique information unobtainable from histopathological, in vitro slice, cell culture, or animal seizure models. Such information may have important implications for effective pharmacological and surgical control of seizures.

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Engel Jr, Jerome (2018) Epileptogenesis, traumatic brain injury, and biomarkers. Neurobiol Dis :
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