Alteration of epileptogenesis genes.
Retrospective studies suggest that precipitating events such as prolonged seizures, stroke, or head trauma increase the risk of developing epilepsy later in life. The process of epilepsy development, known as epileptogenesis, is associated with changes in the expression of a myriad of genes. One of the major challenges for the epilepsy research community has been to determine which of these changes contributes to epileptogenesis, which may be compensatory, and which may be noncontributory. Establishing this for any given gene is essential if it is to be considered a therapeutic target for the prevention or treatment of epilepsy. Our laboratories have examined alterations in gene expression related to inhibitory neurotransmission that have been proposed as contributing factors in epileptogenesis. The GABA(A) receptor mediates most fast synaptic inhibition, and changes in GABA(A) receptor subunit expression and function have been reported in adult animals beginning immediately after prolonged seizures (status epilepticus [SE]) and continue as animals become chronically epileptic. Prevention of GABA(A) receptor subunit changes after SE using viral gene transfer inhibits development of epilepsy in an animal model, suggesting that these changes directly contribute to epileptogenesis. The mechanisms that regulate differential expression of GABA(A) receptor subunits in hippocampus after SE have recently been identified, and include the CREB-ICER, JAK-STAT, BDNF, and Egr3 signaling pathways. Targeting signaling pathways that alter the expression of genes involved in epileptogenesis may provide novel therapeutic approaches for preventing or inhibiting the development of epilepsy after a precipitating insult.
Brooks-Kayal
Amy R
AR
Division of Neurology, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA. brooks-kayal.amy@tchden.org
Raol
Yogendra H
YH
Russek
Shelley J
SJ