Effects of extended kindling in hippocampal and olfactory cortical systems on measures of transfer, inhibition, cell loss and sprouting

Allison E. Spiller

Abstract

Human epilepsies are a family of disorders of the nervous system, characterized by transient, recurring episodes of neuronal hypersynchronous seizure activity. These often begin locally, but they may generalize to produce convulsions. The basic mechanisms responsible for the seizures are unknown, but several animal models of epilepsy are available for the study of the neuronal abnormalities associated with these events. One of these is the kindling model in which repeated application of electrical stimulation to certain brain regions results in the progressive development of electroencephalographic and behavioural seizures.

In this thesis, we compared two excitatory monosynaptic systems for rates of transfer kindling effects, levels and alterations in inhibition, kindling-induced cell loss and mossy fiber sprouting. Animals were kindled for 30 or more stage 5 seizures. The two monosynaptic systems studied were: 1) entorhinal cortex-perforant path-dentate-gyrus system and 2) olfactory bulb-lateral olfactory tract-piriform cortex.

Our major findings may be summarized as follows: a) there was immediate transfer in the olfactory bulb-lateral olfactory tract-piriform cortex system but not in the entorhinal cortex-perforant path-dentate gyrus system. We hypothesized that the difference in transfer rates was due to differences in the spatio-temporal patterns of discharge at the network level. b) In both systems, the levels of inhibition were increased following kindling, remained increased throughout administration of kindling simulations and then returned towards baseline levels after discontinuation of the kindling stimulations. This suggests that a disturbance in the inhibitory system of the dentate gyrus or the piriform cortex can not explain the epileptogenesis. c) We found a decrease in the number of hilar cells of the dentate gyrus following kindling in the entorhinal cortex-perforant path-dentate gyrus system but not following kindling of the olfactory bulb-lateral olfactory tract-piriform cortex system. d) Sprouting of mossy fibers was found into the IML of the dentate gyrus following kindling of the lateral olfactory tract but only after at least 14 stage 5 seizures had been elicited. There was no evidence of sprouting of these fibers into the stratum oriens of area CA3.

These findings suggest that kindling results in a remarkable specificity in the seizure circuitry dependent on the site of stimulation and does not require cell loss in the hilus or mossy fiber sprouting into either the CA3 or the IML for it to occur. Since we found enhanced inhibition in both systems with kindling, a failure of inhibition, at least in these systems, can not explain epileptogenesis.