Abnormal targeting of developing hippocampal mossy fibers after epileptiform activities via L-type Ca2+ channel activation in vitro.

The hippocampal mossy fibers, which originate from the dentate granule cells, develop mainly in the early postnatal period and are involved in numerous pathological processes. In this study, hippocampal slices prepared from premature rats were cultivated in the presence of convulsants to evaluate the influences of epileptiform activities on mossy fiber ontogeny. Electrophysiological and histochemical analyses revealed that prolonged hyperexcitability inhibited proper growth of the mossy fibers and caused ectopic innervation to the stratum oriens and the dentate molecular layer. These phenomena were prevented by pharmacological blockade of L-type Ca2+ channels, which did not affect convulsant-evoked ictal bursts. After single-pulse stimulation of the stratum granulosum in the slices cultured under paroxysmal conditions, the dentate gyrus displayed excessive excitation, but synaptic transmission to the CA3 region was hypoactive. However, brief repetitive stimulation elicited delayed epileptiform discharges in the CA3 region that were inhibited by an NMDA receptor antagonist. Chronic treatment with an L-type Ca2+ channel blocker ameliorated such aberrant neurotransmissions. These results suggest that ictal neuron activities at the developmental stage of the mossy fibers bring about the errant maturation associated with hippocampal dysfunction, which may form a cellular basis for the sequelae of childhood epilepsy, including chronic epilepsy or cognitive deficits. Thus I propose that L-type Ca2+ channel blockers can ameliorate the aversive prognosis of childhood epilepsy.