Excitatory effects of gap junction blockers on cerebral cortex seizure-like activity in rats and mice


Address correspondence to Logan J. Voss, Department of Anesthesiology, Waikato Clinical School, Waikato Hospital, Pembroke St, Hamilton, New Zealand. E-mail: vossl@waikatodhb.govt.nz


Purpose: The role of gap junctions in seizures is an area of intense research. Many groups have reported anticonvulsant effects of gap junction blockade, strengthening the case for a role for gap junctions in ictogenesis. The cerebral cortex is underrepresented in this body of research. We have investigated the effect of gap junction blockade on seizure-like activity in rat and mouse cerebral cortex slices.

Methods: Seizure-like activity was induced by perfusing with low-magnesium artificial cerebrospinal fluid. The effect of three gap junction blockers was investigated in rat cortical slices; quinine (200 and 400 μm), quinidine (100 and 200 μm), and carbenoxolone (100 and 200 μm). In addition, the effect of mefloquine was investigated in wild-type mice and connexin36 knockout mice. The data were analyzed for the effect on frequency and amplitude of seizure-like events.

Results: Paradoxical excitatory effects on seizure-like activity were observed for all three agents in rat cortical slices. Quinine (200 μm) and carbenoxolone (100 μm) increased both the frequency and amplitude of seizure-like events. Quinidine (100 μm) increased the frequency of events. Higher doses of quinine (400 μm) and carbenoxolone (200 μm) had biphasic excitatory–inhibitory effects. Similar excitatory effects were observed in adult wild-type mouse cortical slices perfused with mefloquine (5 μm or 10 μm), but were absent in slices from connexin36-deficient mice.

Discussion: In conclusion, we have shown a paradoxical proseizure effect of pharmacologic gap junction blockade in a cortical model of seizure-like activity. We suggest that this effect is probably due to a disruption of inhibitory interneuron coupling secondary to connexin36 blockade.