Mefloquine prophylaxis after experimental status epilepticus protects against interneuron loss and epileptogenesis

Background: Temporal lobe epilepsy (TLE), a common form of acquired refractory epilepsy, is characterized by spontaneous recurrent seizures (SRS) and hippocampal inhibitory neuron dysfunction. Gap junctional or electrical coupling between inhibitory neurons has been proposed to facilitate network synchrony and intercellular molecular exchange suggesting a role in seizures and neurodegeneration. While gap junction blockers can limit acute seizures, whether blocking neuronal gap junctions can modify development of chronic epilepsy remains unknown. This study examined whether mefloquine, a blocker of gap junctions enriched in inhibitory neurons, can limit epileptogenesis and related cellular and behavioral pathology in a model of acquired TLE. Experimental Approach: Immunohistochemical, electrophysiological and behavioral approaches were used to examine the effect of mefloquine, administered after pilocarpine-induced status epilepticus (SE), on hippocampal inhibitory neuron function and development of SRS. Paired recordings were used to determine the functional impact of status epilepticus on interneuronal electrical coupling. Results: A single, systemic dose of mefloquine administered after SE reduced development of SRS and behavioral co-morbidities. Mefloquine treatment limited inhibitory neuronal loss and preserved inhibitory synaptic drive to projection neurons. SE selectively reduced the probability of electrical coupling between parvalbumin interneurons in the hippocampal dentate gyrus without altering coupling coefficient or coupling frequency between non-parvalbumin interneurons. Conclusion and Implications: The early and selective decrease in electrical coupling between dentate parvalbumin interneurons after status epilepticus, likely limits their excitotoxic damage during epileptogenesis. These results suggest that blocking gap junctional coupling with mefloquine may be neuroprotective and prophylactic against epileptogenesis and behavioral co-morbidities.