Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment

Abstract

In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K+ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca2+ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments.

Effects of Atypical Antipsychotics, Clozapine, Quetiapine and Brexpiprazole on Astroglial Transmission Associated with Connexin43

“…It has been well established the higher vigilance for seizure is warranted during treatment with CLZ and QTP [ 77 , 78 ]. Recently, preclinical findings using several epileptic/convulsive animal models have displayed the possibility that upregulation/hyperfunction of Cx43 contributes to development of epileptogenesis/ictogenesis [ 2 , 10 , 11 , 12 , 22 , 79 , 80 , 81 , 82 ]. Furthermore, pharmacodynamic studies reported that Cx43 is one of the major targets of several anti-seizure agents, zonisamide, lacosamide, brivaracetam and VPA [ 8 , 9 , 11 , 12 , 67 ].…”

“…Furthermore, pharmacodynamic studies reported that Cx43 is one of the major targets of several anti-seizure agents, zonisamide, lacosamide, brivaracetam and VPA [ 8 , 9 , 11 , 12 , 67 ]. Astroglial hemichannel is activated by depolarization and exposure to transient toxic (100 mM) or persistent pathological (10 mM) extracellular K + , and active state of hemichannel continues several hours [ 8 , 9 , 10 , 11 , 12 , 22 , 67 , 79 ]. Therefore, the stimulatory effects of CLZ and QTP on astroglial Cx43 containing hemichannel activity seem to be rational mechanisms regarding the adverse seizure reaction induced by CLZ and QTP.…”

Astroglial Connexin43 as a Potential Target for a Mood Stabiliser

“…Indeed, a nonselective connexin inhibitor, CBX, and Cx43-selective mimetic peptide inhibitors Gap27 and Gap26, induced depression, anhedonia, and anxiety-like behaviour [ 59 ]. These three connexin inhibitors, CBX, Gap26, and Gap27, inhibit both astroglial Cx43-containing gap junction and hemichannel [ 134 ]. However, lacosamide, which inhibits astroglial hemichannel activity without affecting Cx43 synthesis, led to a mild but antidepressant-like effect rather than depressive mood induction [ 116 , 117 , 118 ].…”

Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis

“…In addition, spatial potassium buffering is known to be linked to glutamate uptake via glutamate transporters [e.g., excitatory amino acid transporters 1 (EAAT1) and EAAT2] and water transport via aquaporin-4 (AQP4) by astrocytes (26)(27)(28)(29)(30)(31). Moreover, both connexin30 and connexin43 in astrocytic gap junctions were shown to play a critical role in normal K + redistribution, using double knockout techniques in mice (32,33).…”