Curious and contradictory roles of glial connexins and pannexins in epilepsy

Abstract

Glia play an under-recognized role in epilepsy. This review examines the involvement of glial connexins (Cxs) and pannexins (Panxs), proteins which form gap junctions and membrane hemichannels (connexins) and hemichannels (pannexins), in epilepsy. These proteins, particularly glial Cx43, have been shown to be upregulated in epileptic brain tissue. In a cobalt model of in vitro seizures, seizures increased Panxs1 and 2 and Cx43 expression, and remarkably reorganized the interrelationships between their mRNA levels (transcriptome) which then became statistically significant. Gap junctions are highly implicated in synchronous seizure activity. Blocking gap junctional communication (GJC) is often anticonvulsant, and assumed to be due to blocking gap junctionally-medicated electrotonic coupling between neurons. However, in organotypic hippocampal slice cultures, connexin43 specific peptides, which attenuate GJC possibly by blocking connexon docking, diminished spontaneous seizures. Glia have many functions including extracellular potassium redistribution, in part via gap junctions, which if blocked, can be seizuregenic. Glial gap junctions are critical for the delivery of nutrients to neurons, which if interrupted, can depress seizure activity. Other functions of glia possibly related to epileptogenesis are mentioned including anatomic reorganization in chronic seizure models greatly increasing the overlapping domains of glial processes, changes in neurotransmitter re-uptake, and possible glial generation of currents and fields during seizure activity. Finally there is recent evidence for Cx43 hemichannels and Panx1 channels in glial membranes which could play a role in brain damage and seizure activity. Although glial Cxs and Panxs are increasingly recognized as contributing to fundamental mechanisms of epilepsy, the data are often contradictory and controversial, requiring much more research. This article is part of a Special Issue entitled Electrical Synapses.