ABSTRACT
Most research on the generation and propagation of seizures and on the mechanisms of epileptogenesis has centered around the role of chemical synaptic transmission, specifically the glutamatergic and GABA-ergic systems. Research on the role of nonsynaptic mechanisms in epilepsy, particularly in the synchronization of electrical activity during seizures, has a long and controversial history. Over 15 years ago, electrical mechanisms of neuronal interaction were proposed to play an important role in synchronization during epileptiform activity (see 1, 2 for reviews), and comparable analyses of the potential role of ionic mechanisms were also available (3, 4). The widely used expression “nonsynaptic” has come to refer to those mechanisms that are independent of active chemical synaptic transmission. One mechanism included in this description would be electrotonic coupling through gap junctions, which many workers would consider to be electrical synapses (5-7). Another mechanism is electrical-field effects (i.e., ephaptic interactions), which are mediated by current flow in the extracellular space. These two mechanisms are distinctly different because the former involves a specialized membrane structure (i.e., gap junctions, which are intercellular channels composed of connexin proteins), whereas the latter is due to neuronal orientation and the size of the extracellular space (i.e., tightly packed neurons that are arranged in parallel are susceptible to the effects of activity-induced electrical fields). A third mechanism involves activity-dependent shifts in the intracellular and extracellular concentration of ions. The intense electrical activity of seizures is associated with transmembrane ionic currents, which cause a redistribution of ions such as potassium and calcium. Increases in the concentration of extracellular potassium and decreases in extracellular calcium, both of which would usually increase membrane excitability, would have a slow synchronizing effect on neurons in a network. The goal of this chapter is to summarize (1) the evidence for the presence of these mechanisms in the hippocampus, (2) their possible role in synchronization of electrical activity during seizures, and (3) how these mechanisms may be targets for clinical intervention. It should
be noted that nonsynaptic interactions amongst neocortical neurons may not be as relevant owing to their lower packing density and relative lack of gap junctions.
