Roles of gap junctions, connexins, and pannexins in epilepsy

Abstract

Enhanced gap junctional communication (GJC) between neurons is considered a major factor underlying the neuronal synchrony driving seizure activity. In addition, the hippocampal sharp wave ripple complexes, associated with learning and seizures, are diminished by GJC blocking agents. Although gap junctional blocking drugs inhibit experimental seizures, they all have other non-specific actions. Besides interneuronal GJC between dendrites, inter-axonal and inter-glial GJC is also considered important for seizure generation. Interestingly, in most studies of cerebral tissue from animal seizure models and from human patients with epilepsy, there is up-regulation of glial, but not neuronal gap junctional mRNA and protein. Significant changes in the expression and post-translational modification of the astrocytic connexin Cx43, and Panx1 were observed in an in vitro Co ++ seizure model, further supporting a role for glia in seizure-genesis, although the reasons for this remain unclear. Further suggesting an involvement of astrocytic GJC in epilepsy, is the fact that the expression of astrocytic Cx mRNAs (Cxs 30 and 43) is several fold higher than that of neuronal Cx mRNAs (Cxs 36 and 45), and the number of glial cells outnumber neuronal cells in mammalian hippocampal and cortical tissue. Pannexin expression is also increased in both animal and human epileptic tissues. Specific Cx43 mimetic peptides, Gap 27 and SLS, inhibit the docking of astrocytic connexin Cx43 proteins from forming intercellular gap junctions (GJs), diminishing spontaneous seizures. Besides GJs, Cx membrane hemichannels in glia and Panx membrane channels in neurons and glia are also inhibited by traditional gap junctional pharmacological blockers. Although there is no doubt that connexin-based GJs and hemichannels, and pannexin-based membrane channels are related to epilepsy, the specific details of how they are involved and how we can modulate their function for therapeutic purposes remain to be elucidated.

Coupled Oscillators Model of Hyperexcitable Neuroglial Networks

“…The gap junctions of the astrocytes were also found to affect the hyperexcitability of the system. This has been demonstrated in studies of cerebral tissue from animal seizure models and human patients, where there was an up-regulation of glial gap junctional mRNA and protein [128].…”

Regulation of Connexins Expression Levels by MicroRNAs, an Update

“…Changes in expression levels and/or channel function formed by several different Cxs have been associated with a number of central nervous system (CNS) disorders. Among these, we can mention X-linked Charcot-Marie-Tooth disease (Bergoffen et al, 1993), traumatic injury of the brain and/or spinal cord (Cronin et al, 2008), hypersynchronous neuronal activity associated with seizures (Seifert et al, 2010; Mylvaganam et al, 2014), and several others (Retamal et al, 2015; Xie et al, 2015). Treatment with a mimetic peptide reduces tissue damage by downregulating gliosis and cytokine release (O'Carroll et al, 2013).…”

Regulation of the Pannexin-1 Promoter in the Rat Epididymis1

“…PANX1 in the hippocampus has also been associated with murine models of epilepsy. Studies have shown that PANX1 levels are increased in epilepsy, and that the N-methyl-D-aspartate receptor can activate the opening of PANX1 channels, thereby raising extracellular ATP [39] and arachidonic acid levels, and promoting epileptiform activity [19,[34][35][36][37].…”