We have developed an experimental model which may help to unravel the complexities associated with propagation of focal epileptiform discharges and the production of seizures. We modified the kindling model of epilepsy to concurrently develop two seizure foci instead of one and observed the surprising result that one focus assumed dominance and developed generalized seizures, while the other focus became suppressed. We call this model """"""""kindling antagonism."""""""" Our first two specific aims are to use this model to assess the relevance of two mechanisms postulated to underlie kindled seizure development. The first is enhancement of excitation involving synaptic postactivation long-term potentiation (LTP). Kindling antagonism allows for a more direct test of LTP as a mechanism of kindled seizure development. For LTP to be considered a viable mechanism, it must be present in the efferent pathway of the dominant focus, but not in that of the suppressed focus. The second mechanism is disinhibition involving the breakdown of a seizure-inhibiting substrate mediated by catecholamines, particularly nonrepinephrine. If one postulates that catecholamines normally suppress seizure development, then it follows that catecholamines may also be responsible for the suppression of seizure development during kindling antagonism. We will test this by determing if catecholamine depletion abolishes antagonism. We will also determine the effect of catecholamine depletion on dominance between foci. Our final specific aim is to expand our basic knowledge of the phenomenon of kindling antagonism which, we believe, can provide significant insight into how seizures propagate. Specific questions we will ask are the following: (1) Does antagonism involve the participation of brainstem mechanism? (2) Is antagonism specific to the suppressed focus or is there a more widespread action affecting the seizure susceptibility of other limbic structures? (3) What is the effect of concurrent kindling from 3 or more foci? (4) What is the extent of seizure development occurring from the suppressed focus? We believe that by understanding some of the brain's own mechanisms for suppressing seizure development we may be able to work in concert with them in designing therapeautic approaches, both pharmacological and surgical.
| Ferland, R J; Nierenberg, J; Applegate, C D (1998) A role for the bilateral involvement of perirhinal cortex in generalized kindled seizure expression. Exp Neurol 151:124-37 |
| Applegate, C D; Jensen, F; Burchfiel, J L et al. (1996) The effects of neonatal hypoxia on kindled seizure development and electroconvulsive shock profiles. Epilepsia 37:723-7 |
| Waszczak, B L; Applegate, C D; Burchfiel, J L (1988) Kindling does not cause persistent changes in firing rates or transmitter sensitivities of substantia nigra pars reticulata neurons. Brain Res 455:115-22 |
