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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Disorders Program Project Review B Committee (NSPB)
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University of Washington
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Spain, W J (1994) Serotonin has different effects on two classes of Betz cells from the cat. J Neurophysiol 72:1925-37
Schwindt, P C; Spain, W J; Crill, W E (1992) Calcium-dependent potassium currents in neurons from cat sensorimotor cortex. J Neurophysiol 67:216-26
Schwindt, P C; Spain, W J; Crill, W E (1992) Effects of intracellular calcium chelation on voltage-dependent and calcium-dependent currents in cat neocortical neurons. Neuroscience 47:571-8
Spain, W J; Schwindt, P C; Crill, W E (1991) Post-inhibitory excitation and inhibition in layer V pyramidal neurones from cat sensorimotor cortex. J Physiol 434:609-26
Spain, W J; Schwindt, P C; Crill, W E (1991) Two transient potassium currents in layer V pyramidal neurones from cat sensorimotor cortex. J Physiol 434:591-607
Schwindt, P C; Spain, W J; Crill, W E (1989) Long-lasting reduction of excitability by a sodium-dependent potassium current in cat neocortical neurons. J Neurophysiol 61:233-44
Schwindt, P C; Spain, W J; Foehring, R C et al. (1988) Slow conductances in neurons from cat sensorimotor cortex in vitro and their role in slow excitability changes. J Neurophysiol 59:450-67
Schwindt, P C; Spain, W J; Crill, W E (1988) Influence of anomalous rectifier activation on afterhyperpolarizations of neurons from cat sensorimotor cortex in vitro. J Neurophysiol 59:468-81