Role of gap junctions in epilepsy

Abstract

Epilepsy is a common neurological disorder characterized by periodic and unpredictable seizures. Gap junctions have recently been proposed to be involved in the generation, synchronization and maintenance of seizure events.The present review mainly summarizes recent reports concerning the contribution of gap junctions to the pathophysiology of epilepsy, together with the regulation of connexin after clinical and experimental seizure activity. The anticonvulsant effects of gap junction blockers both in vitro and in vivo suggest that the gap junction is a candidate target for the development of antiepileptic drugs. It is also of interest that the roles of neuronal and astrocytic gap junctions in epilepsy have been investigated independently, based on evidence from pharmacological manipulations and connexin-knockout mice.Further studies using more specific manipulations of gap junctions in different cell types and in human epileptic tissue are needed to fully uncover the role of gap junctions in epilepsy.

Effects of meclofenamic acid on limbic epileptogenesis in mice kindling models

“…Accumulating evidence indicates that gap junctions may be involved in epileptogenesis. Changes of expression of Cx43 and Cx36, the main connexins forming gap junctions in astrocytes and neurons respectively, are observed in both human epileptic brain regions and animal epileptogenic models [7]. Astroglial gap junctions are proved to deliver energetic metabolites from blood vessels to distal neurons to sustain glutamatergic synaptic transmission and epileptiform activity [19] and long-term block of astrocytic gap junctions through Cx43 mimetic peptides attenuated spontaneous seizure like events in organotypic hippocampal slice cultures [20].…”

“…Gap junctions, composed of connexin (Cx) subunits, are intercellular membrane channels that provide direct cytoplasmic continuity between adjacent cells and allow propagation of electrical impulses and exchange of small molecules [7]. An increasing number of studies suggest that gap junctions in the brain may be involved in the process of epileptogenesis [7,19,23,26].…”

“…An increasing number of studies suggest that gap junctions in the brain may be involved in the process of epileptogenesis [7,19,23,26]. Synchronous neuronal networks connected by gap junctions are important in the generation of high-frequency oscillations (HFOs), which are an indication of an epileptiform network mechanism in epileptogenesis [23].…”

“…Astrocytic gap junctions can influence the balance of neuronal microenvironments by buffering extracellular K + and delivering energetic metabolites, which in turn affect neuron functions during seizure events [19,26]. Changes of connexins mRNA and protein are also observed in limbic regions in electrical kindling and post-status epilepticus models [7]. Thereby gap junctions may be a potential drug target to interfere epileptogenesis.…”

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

“…At least 11 of the 21 human Cx genes are expressed in the nervous system, with different cell specificity GJ intercellular communication is particularly extended among glia, but GJs are also abundantly present in neurons [85]. An elevated level of Cx43 mRNA has been shown in samples of temporal lobe neocortex, surgically resected for DRE, whereas much lower levels of this mRNA were detectable in peri-tumoural temporal lobe tissue samples obtained during removal of cerebral tumours [86]. Similar changes but with less dramatic difference were observed for the mRNA of Cx32, suggesting an increase in the synthesis of GJ protein that may lead to an increase in intercellular coupling, in the temporal cortex of patients exhibiting seizure disorders.…”