Mechanisms of Hyperexcitability in the Kindling Model of Epilepsy

Sammanfattning: Epilepsy is a syndrome characterized by recurring attacks of sudden, excessive and synchronous discharge in populations of cerebral neurons. Kindling is an animal model for complex partial epilepsy, and is particularly useful for studies on the development of the abnormal excitability underlying the generation and spread of epileptic seizures. Here we have used the kindling model to investigate mechanisms important for the development of hyperexcitability, with particular emphasis on the role of neurotrophic factors and hippocampal synaptic reorganization. We demonstrate for the first time that a brief period of stimulus-evoked recurring seizures can trigger a long-term increase of excitability, which develops in two phases: an acute, transient, and a late phase developing gradually over a 4 week period. This type of rapidly recurring seizures induced delayed epileptogenesis in a strain of genetically fast but not slow kindling rats. Comparisons between these two strains and normal rats suggest that long duration of individual focal seizures during the initial stimulation procedure plays a more important role than, e. g., seizure generalization and total seizure duration for the delayed increase in excitability. Results from the studies presented here in neurotrophin knockout mice, indicate a facilitatory role for the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 in kindling epileptogenesis. Using a recently developed enzyme immonoassay, prominent alterations in BDNF protein levels were detected following single and recurring kindling-induced seizures in various forebrain regions important for seizure generation and spread. Granule cell mossy fiber sprouting to the inner molecular layer of the dentate gyrus developed in parallel to increased excitability following both traditional kindling and recurring seizures. Kindling epileptogenesis could be evoked without sprouting in genetically slow and fast kindlers, suggesting that mossy fiber sprouting does not play a crucial facilitatory role in epileptogenesis. Directly supporting an inhibitory action of mossy fiber reorganization in epileptogenesis was the finding that non-stimulated genetically slow animals had a more dense projection of mossy fibers to the inner molecular layer as compared to fast animals. The results of the present thesis suggest that attenuation of neurotrophin responses after seizures and other brain insults, such as traumatic injury, might have an antiepileptogenic action. In addition, the findings of delayed epileptogenesis after recurring seizures might initiate future pharmacological intervention for the prevention of chronic epilepsy following head trauma or status epilepticus in patients.