Single-gene models of epilepsy.

Single-gene models of epilepsy present valuable opportunities to isolate and experimentally reproduce gene mutations for human seizure disorders, to test molecular mechanisms of epileptogenesis, and to explore strategies to correct early hyperexcitability defects in the developing brain. Although not all inherited epilepsies are monogenic, analysis of epileptic phenotypes in spontaneous and transgenic mouse mutants is beginning to define the kinds of molecular defects favoring inherited aberrant synchronization in central neurons. The range of genes identified shows that rather than arising from a few superfamilies that regulate membrane excitability, the gene products are drawn from many categories involved in widely diverse functions of the cell. Although some primary defects directly alter membrane electrogenesis and neurotransmitter signaling at synapses, others are too far removed from these processes to allow one to visualize the steps by which they promote epileptogenesis. There is now clear evidence that several and probably most epilepsy genes entrain specific patterns of secondary cellular plasticity during brain development. It can be predicted that these downstream rearrangements may partially account for the delayed temporal onset and other progressive features of epilepsy syndromes. Experimental alterations that target the mutant gene product and patterns of secondary network plasticity provide a basis for future strategies to reverse the epileptogenic process.