The kindling model of epilepsy: A critical review

These clinical observations notwithstanding, one striking difference exists between kindling and human epilepsy, namely, the absence of a histologically detectable lesion in the brains of kindled animals. In contrast, lesions, often including Ammon's horn sclerosis, are readily detectable with standard histologic techniques in the majority of temporal lobes resected from patients with medically intractable complex partial epilepsy. ⁷⁴Epileptologists have long speculated that these lesions may somehow increase local neuronal excitability, which in turn would contribute to human epileptogenesis. Studies of Ammon's horn sclerosis induced by the excitation, kainic acid, lend support to this idea. The principal targets of the axons of the dentate granule cells of hippocampal formation are the CA3 pyramidal cells. These axons exert a powerful excitatory influence on the CA3 cells. Destruction of some of these CA3 pyramidal cells deprives the granule cells of their normal targets. One consequence is that the axons of the granule cells appear to form synapses on their own cell bodies and proximal dendrites, an alteration which could result in a recurrent excitatory synapse.¹⁸⁷ Studying hippocampal slices removed from animals with kainic acid lesions, Nadler and colleagues ¹⁸⁸ have demonstrated repetitive firing of granule cells in response to a single orthodromic excitatory pulse. Such repetitive firing was not observed in slices from control animals. This could lead to repetitive and excessive firing of granule cells in response to a physiologic afferent input. We speculate that such repetitive firing could kindle target structures in a pattern similar to that observed in the kindling model. The presence of spontaneous seizures months after a single treatment with kainic acid supports this idea. If correct, this hypothesis would predict that the presence of Ammon's horn sclerosis induced by hypoxic damage in infancy or adulthood would increase the risk of developing epilepsy. Moreover, since repeated seizures can induced Ammon's horn sclerosis in experimental animals, this model might explain the apparent progression of the epileptic condition observed in some patients after frequent seizures.