Possible roles of nonsynaptic mechanisms in synchronization of epileptic seizures: Potential antiepileptic targets?

This review describes nonsynaptic mechanisms that likely play an important role in synchronization of neuronal electrical activity during seizures and may contribute to chronic epilepsy. Both electrotonic coupling through gap junctions and electrical field effects (i.e., ephaptic interactions) via currents in the extracellular space can synchronize action potentials and are probably important in the high-frequency oscillations (i.e., “fast ripples”) seen at seizure onset in humans with temporal lobe epilepsy and in animal models. Robust seizure-like activity can be generated in hippocampal slices after active chemical transmission is blocked with either low-calcium solutions or with γ-aminobutyric acid (GABA)- and glutamate-receptor antagonists. Gap junction blockers and treatments that increase the size of the extracellular space suppress or block this type of seizurelike activity. Research in this area may lead to approaches that block seizures without negatively impacting normal brain function, as compared to drugs that alter neurotransmitter systems (e.g., glutamatergic or GABAergic mechanisms). Relatively few data are available regarding the hypothesis that nonsynaptic mechanisms underlie or contribute to chronic epileptogenesis (i.e., spontaneous recurrent seizures from genetic mutations or after brain injury), and additional experiments are required to test this hypothesis.