Roles of gap junctions, connexins, and pannexins in epilepsy.

Shanthini Mylvaganam,Michal Krawczyk,Meera Ramani,Peter L. Carlen

doi:10.3389/fphys.2014.00172

Shanthini Mylvaganam, Michal Krawczyk + Show 2 more

Open Access

https://doi.org/10.3389/fphys.2014.00172

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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.

Highlights

When one thinks of the “connections” between epilepsy and gap junctions (GJs), the usual interpretation is that the GJs form direct intercellular cytoplasmic connections between neurons, promoting the hypersynchronous neuronal activity associated with seizures
Kang showed that P2X7R-Panx1 complex may play an important role as a negative modulator of M1 receptor-mediated seizure activity in vivo, since they showed pilocarpine-induced seizures in mice were enhanced following administration of P2X7R antagonists or by gene silencing of P2X7R or Panx1 in WT in a process mediated by PKC via intracellular Ca2+ release (Kim and Kang, 2011)
The gap junctional blocking drugs are almost always anticonvulsant, there is not as of yet an anticonvulsant drug on the market that is reputed to have gap junctional blocking properties, both acetazolamide and topiramate inhibit carbonic anhydrase activity which should cause an intracellular acidosis thereby blocking gap junctional communication (GJC). Another problem is the overwhelming evidence that tissue from animal models and human epileptics show increases in Cxs expression in glia but not in neurons

Summary

Introduction

When one thinks of the “connections” between epilepsy and gap junctions (GJs), the usual interpretation is that the GJs form direct intercellular cytoplasmic connections between neurons, promoting the hypersynchronous neuronal activity associated with seizures. An in vivo and ex-vivo study of adult rats treated with 4aminopyridine (4-AP), a K+ channel blocker which induces seizures, have shown that dephosphorylation of connexin 43 associated with astrocytic swelling, resulted in reduction of astrocytic gap junction permeability (Zador et al, 2008).

Results

Conclusion