The long term objectives of the research proposal are to answer the question, what are the mechanisms underlying the spread of focal seizures through normal neocortex? Specifically, what role do neurotransmitters play, what is the influence of extracellular potassium ions (K+) and are there changes in neuron membrane properties that facilitate the process? Epilepsy affects approximately 5% of the population. The mechanisms of how focal seizures spread are partially understood. A more complete unraveling of the mechanisms will lead to better methods of therapeutic intervention in the treatment of epileptic patients. Work towards answering these questions will utilize in vitro slices of mammalian pericruciate cortex. Large layer V pyramidal cells (Betz cells) will be impaled for intracellular microelectrode recording and single electrode voltage clamp (SEVC). Some studies will also use specific channel blocker, ionic substitutions and iontophoresis of neurotransmitters. Initially, the effects on firing properties of excitatory amino acids, and neuropeptides will be studied and the underlying ionic currents evaluated with SEVC. The effects of increased (K+)o on firing properties and subthreshold ionic currents and its effects on transmitter release and Betz cell response to synaptic input will likewise be evaluated. Finally, a model for focal seizures will be developed in the neocortical slices using electrical stimulation. Betz cells will be studied before, during and after seizures, specifically looking at changes in synaptic transmission, alterations of membrane properties, an the influence of (K+) on the propagation of the seizure activity through normal Betz cells.
