Date of Award
Doctor of Philosophy (PhD)
Professor R.J. Racine
Repeated electrical stimulations of the brain via a chronically implanted electrode induce gradually stronger epileptiform responses until the animals show fully developed bilateral clonic convulsions. This experimental epilepsy model is called kindling. Most of the experiments done on this phenomenon have compared kindled to non-kindled animals. Consequently, the changes observed are often secondary, rather than primary, to the developing epileptogenesis.
As an alternative approach, two strains of rats were outbred from a common parent generation on the basis of amygdala kindling rates (the number of evoked epileptiform discharges (ADs) required to reach the fully developed seizure stage). After 5 generations, we succeeded in producing two groups of rats that demonstrated no overlap in amygdala kindling rates. Kindling-prone or FAST rats required 11.0 ADs, whereas kindling-resistant or SLOW rats required 42.1 AD. to develop fully generalized seizures.
We have used electrophysiological and pharmacological tests in an attempt to determine the mechanisms underlying the differences in epileptogenesis in these two strains.
The electrophysiological experiments were designed to test the hypothesis that FAST rats have either a greater plasticity in excitatory neural systems, or a faster rate of alteration in those systems. Both short-term and long-term potentiation effects were examined in 2 different forebrain pathways. The results did not support the hypothesis. Rather, the results indicated that FAST rats may have lower levels of inhibition, as reflected in measures of paired-pulse depression.
Pharmacological experiments were performed in order to challenge specific inhibitory neurotransmitter systems. The results indicated that FAST rats had significantly lower thresholds for convulsants that are known to interfere with GABA-related inhibitory mechanisms. A preliminary study of GABA receptors, however, showed that [³H]-Muscimol binding did not differ between the strains.
It was argued that FAST rats may be deficient, relative to SLOW rats, in levels of inhibition mediated by other than GABA neurotransmitter systems, or that they may differ in membrane mechanisms that mediate late after hyperpolarizations.
Steingart, Madoka Oshima, "The Selective Breeding of Seizure-Prone vs. Seizure-Resistant Rats Based on Amydaloid Kindling: Behavioral, Electrophysiological and Pharmacological Measures" (1983). Open Access Dissertations and Theses. Paper 1325.