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The Journal of Neuroscience, January 15, 1999, 19(2):802-812
Abnormal Targeting of Developing Hippocampal Mossy Fibers after
Epileptiform Activities via L-type Ca2+ Channel Activation
In Vitro
Yuji
Ikegaya
Laboratory of Chemical Pharmacology, Graduate School of
Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
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.
Key words:
hippocampus; dentate gyrus; mossy fiber; childhood
epilepsy; granule cell; L-type Ca2+ channel; sprouting; axon guidance; targeting
Copyright © 1999 Society for Neuroscience 0270-6474/99/192802-11$05.00/0
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