Cell death and synaptic reorganizations produced by seizures

The events that follow epilepsy seizures are not restricted to the immediat e period. A series of long-term alterations occurs, including synaptic rear rangements, which have an impact on the brain circuit's mode of operation. With models of temporal lobe epilepsy, seizures have been shown to Generate lon-lasting changes in synaptic efficacy (epileptic long-term potentiation ) because of removal of the magnesium block, activation of N-methyl-D-aspar tate receptors, and an increase in intracellular calcium. This novel form o f 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 experime nts clearly indicate that even brief seizures produce changes in synaptic e fficacy, followed 2-3 weeks later by aberrant neosynapse formation. Several key steps have been identified in the cascade leading from transient hyper activity episodes to long-lasting, quasi-permanent modification of the neur onal circuit organization. These include the activation of immediate-early genes, activation of growth factor,genes within hours, alterations in gluta mate receptors, glial hypertrophy, and cytoskeletal protein changes. The ca scade is activated by the increase in intracellular calcium and leads to ax onal growth and neosynapse formation, which in turn participates in the eti ology of the syndrome by reducing the threshold for further seizures. In su mmary, study data imply that the mature epileptic circuit has unique featur es in comparison with those present before a seizure episode, including new receptors, ionic channels, and other proteins. It is therefore essential t o develop novel strategies based on the unique mode of operation of the mat ure epileptic circuit, rather than on acute models of epilepsy.