Consequences of Brain Injury

Head trauma and brain injury are significant factors in the etiology of some epilepsies, but the underlying mechanisms have received little attention. The percentage of all victims of a serious head injury that go on to develop posttraumatic epilepsy has been estimated at 10 to 34%, depending on the severity of the injury. One of the strongest predictors of the likelihood of posttraumatic epilepsy is a penetration of the dura (Willmore, 1990). A striking characteristic of post-traumatic epilepsy is the variable delay between the trauma itself and the development of seizures, which can last from weeks to years. Following head trauma, some relatively slow processes must be triggered, ultimately building to a permanently epileptic state. We have used organotypic hip-pocampal slice cultures to develop an in vitro model of post-traumatic epilepsy that allows the mechanisms underlying the development of hyperexcitability to be investigated under carefully controlled in vitro conditions (McKinney et al., 1997). Lesions of the Schaffer collateral axons of CA3 pyramidal cells in hippocampal slice cultures were made using a razor blade shard after the cultures had been allowed to develop in vitro for more than 14 days. Although the hippocampus is almost never involved in human posttraumatic epilepsy, its beautiful organization allows the presynaptic and postsynaptic consequences of injury to be studied in isolation: CA3 cells undergo a selective axonal injury, whereas CA1 cells undergo a selective partial denervation.

Presynaptic Changes after Injury

An important clue about the nature of the lasting changes underlying the genesis of posttraumatic epilepsy was the discovery that considerable axonal reorganization can occur in the adult brain in response to neuronal injury. For CNS neurons, this process has been studied almost exclusively for the mossy fiber axons of dentate granule cells because of the ease and specificity with which they are labeled using the Timm's stain (Danscher and Zimmer, 1978). The mossy fiber axons of dentate granule cells have been shown to develop supragranular collaterals in the dendritic region of the dentate gyrus in various rodent models of epilepsy as well as in the hippocampi removed from patients undergoing anterior lobectomy for drug refractory, partial complex epilepsy (Houser, 1999; Sutula et al., 1988, 1989). Physiologic studies indicate that the net effect of this sprouting is to increase the excitability of the tissue (e.g., Buckmaster and Dudek, 1999).

Our study of injury after Schaffer collateral transection in slice cultures indicates that pyramidal cells may also regenerate after axonal injury (McKinney et al., 1997). We first filled living CA3 pyramidal cells with biocytin to visualize the morphology of individual cells. Axons extending away from the lesion toward the dentate gyrus were largely

Miniature excitatory postsynaptic currents control

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