Cell Death and Synaptic Reorganizations Produced by Seizures

The events that follow epilepsy seizures are not restricted to the immediate period. A series of long-term alterations occurs, including synaptic rearrangements, which have an impact on the brain circuit's mode of operation. With models of temporal lobe epilepsy, seizures have been shown to generate long-lasting changes in synaptic efficacy (epileptic long-term potentiation) because of removal of the magnesium block, activation of N-methyl-D-aspartate receptors, and an increase in intracellular calcium. This novel form of synaptic plasticity provides a link between memory effects and pathologic processes. Additionally, high-affinity kainate autoradiography, Timm stain, intraventricular injection of kainic acid, and 3D reconstruction experiments clearly indicate that even brief seizures produce changes in synaptic efficacy, followed 2-3 weeks later by aberrant neosynapse formation. Several key steps have been identified in the cascade leading from transient hyperactivity episodes to long-lasting, quasi-permanent modification of the neuronal circuit organization. These include the activation of immediate-early genes, activation of growth factor genes within hours, alterations in glutamate receptors, glial hypertrophy, and cytoskeletal protein changes. The cascade is activated by the increase in intracellular calcium and leads to axonal growth and neosynapse formation, which in turn participates in the etiology of the syndrome by reducing the threshold for further seizures. In summary, study data imply that the mature epileptic circuit has unique features in comparison with those present before a seizure episode, including new receptors, ionic channels, and other proteins. It is therefore essential to develop novel strategies based on the unique mode of operation of the mature epileptic circuit, rather than on acute models of epilepsy.