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

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 mu m), quinidine (100 and 200 mu m), and carbenoxolone (100 and 200 mu m). 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 mu m) and carbenoxolone (100 mu m) increased both the frequency and amplitude of seizure-like events. Quinidine (100 mu m) increased the frequency of events. Higher doses of quinine (400 mu m) and carbenoxolone (200 mu m) had biphasic excitatory-inhibitory effects. Similar excitatory effects were observed in adult wild-type mouse cortical slices perfused with mefloquine (5 mu m or 10 mu m), 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.