Although considered for over three decades, the role of extracellular potassium ([K+]o) in the pathophysiology of seizures is not resolved. This is especially true for events associated with epilepsy, viz. chronic seizures and status epilepticus. More recently alterations of extracellular calcium ([Ca++]o have also been implicated in epileptogenesis, but even less is known about this area than about [K+]o. In the past few years we have developed three models of epilepsy that utilize electrical stimulation in the hippocampus (HC): 1) rapid kindling; 2) acute self-sustaining limbic status epilepticus (SSLSE) induced by preceding continuous hippocampal stimulation (CHS); and 3) spontaneous, recurrent seizures as a sequela to CHS-induced SSLSE. Recently, we adapted these models for use in the urethane-anesthetized rat, thereby allowing us to investigate cellular events and to measure [K+]o and [Ca++]o in the various epileptic conditions just enumerated. Our data indicate that critical displacements of [K+]o and/or [Ca++]o from resting levels are key factors in the generation of certain epileptiform events. Additional data indicates that the distribution of these displacements over the spatial domain of somata and dendrites of dentate gyrus (DG) granule cells is also important for the initiation of a unique and important type of epileptiform discharge--maximal dentate activation (MDA). MDA has been identified as a means to monitor the dynamic process of rapid kindling, as a marker of the chronic kindled state, and as an indicator of self-sustaining and enhancing reverberatory epileptic discharges throughout the HC-paraHC circuit. In fact, MDA is a potent substrate for kindling. Our other studies indicate that the DG and the entorhinal cortex (EC) are critical control points for generation of seizures in this circuit and that these controls depend on NMDA receptor-channel complex activation. The work proposed in this application will examine ionic and associated cellular mechanisms in kindling and the expression of chronic kindled seizures, focusing on the EC and DG as control points in the HC-paraHC circuit. An integrated in vivo and in vitro approach will be used to test four hypotheses: Hypothesis 1 - The onset of reverberatory epileptiform activity in the HC-paraHC circuit is associated with the development of self-sustaining paroxysms in the EC; Hypothesis 2 - The development of MDA involves co-activation of two excitatory inputs to DG granule cells; terminals from hilar mossy cells serve as a trigger factor allowing paroxysms propagating from the EC over the perforant path to drive granule cells in MDA discharges; Hypothesis 3 - The initiation of MDA depends on critical changes in [K+]o and/or [Ca++]o; Hypothesis 4- The development of HC-paraHC circuit reverberatory epileptiform discharges involves activation of NMDA receptor-channel complexes. Data from this work will provide insight into the basic pathophysiology of epilepsy, into how to better treat this condition, and into how to attenuate the chronic brain dysfunction and brain damage that often accompany epilepsy.
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