EXCEED THE SPACE PR_tBEB.. The proposed experiments use an in vivo model for partial epilepsy of temporal lobe origin to test hypotheses regarding the spread of seizure into normally functioning cortex from areas with epileptogenic abnormalities. Studies in vitro have identified many processes that are potentially involved; determining which of these are actually involved and how they contribute will require studies in intact animals that build on findings from in vitro analysis. The experiments will be performed on rat piriform cortex (PC) where partial seizures that secondarily generalize can be readily recruited in behaving animals by activity emanating from a small disinhibited focus. This same process can be duplicated under urethane anesthesia, enabling analytical study in vivo. Electrographic seizures are recruited when normal PC and adjoining limbic cortex are subjected to several seconds of low rate (3-4 Hz) rhythmic excitatory volleys generated by interictal-like discharges in a distant disinhibited focus. A detailed working hypothesis has been developed for the cascade of processes that underlies this transformation. Features of the hypothesis include: (1) K* plays a causal role for seizure spread into normal cortex (despite evidence to the contrary for seizure initiation). (2) Mechanisms for recruitment of seizure in hippocampus differ from those in most other limbic areas including PC. These stem from the lack of an inwardly rectifying cr channel (CIC-2) that regulates somatic-region CI- in hippocampal pyramidal cells but not in PC and many other limbic areas, and glial-like inwardly-rectifying K channels that are weak or absent in hippocampal neurons but present in PC and other limbic areas. (3) Based on our findings from current source-density (CSD) analysis and transmembrane potential recordings in vivo, we propose that ephaptic-field transmission plays a central role in the generation of ictal activity by allowing high-rate, self-sustained discharges to occur after synaptic transmission is attenuated by depletion of docked synaptic vesicles and other factors. A key method is CSD analysis with a 22-site silicon probe that allows rapidly-evolving dendritic-region as well as somatic-region membrane currents to be visualized. Propagation of ephaptic-field driven discharges will be studied using new approaches for 2- and 3- dimensional CSD analysis. These experiments will provide essential information about the spread of epileptic activity into normal cortex, and clues concerning how this spread can be curtailed. PERFORMANCE SiTE ========================================Section End===========================================
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