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The Journal of Neuroscience, June 15, 2003, 23(12):5381-5390
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Short-Term Frequency-Dependent Plasticity at Recurrent Mossy Fiber Synapses of the Epileptic Brain
Li Feng, Peter Molnár, andJ. Victor Nadler Departments of Pharmacology and Cancer Biology and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710
The recurrent mossy fiber pathway of the dentate gyrus expands dramatically in human temporal lobe epilepsy and in animal models of this disorder, creating monosynaptic connections among granule cells. This novel granule cell network can support reverberating excitation but is difficult to activate with low-frequency stimulation. This study used hippocampal slices from pilocarpine-treated rats to explore the dependence of synaptic transmission in this pathway on stimulus frequency. Minimal electrically evoked EPSCs exhibited a high failure rate (
60%). Stimulus trains delivered at a frequency of <1 Hz depressed synaptic transmission, as evidenced by an increase in response failures. Conversely, stimulus trains delivered at higher frequencies reduced the percentage of response failures and increased the amplitude of compound EPSCs, including pharmacologically isolated NMDA receptor-mediated EPSCs. Short-term frequency-dependent facilitation was of modest size compared with mossy fiber synapses on other neuronal types. Facilitation depended on the activation of kainate receptors by released glutamate and was inhibited by feedback activation of type II metabotropic glutamate receptors. These results suggest that the recurrent mossy fiber pathway may be functionally silent during baseline asynchronous granule cell activity in vivo attributable, in part, to progressive transmission failure. The pathway may synchronize granule cell firing and may promote seizure propagation most effectively during the brief periods of high-frequency granule cell firing that occur during normal behavior, during the periods of hypersynchronous fast activity characteristic of epileptic brain and, most importantly, during the period of increasing granule cell activity that precedes a spontaneous seizure.
Key words: epilepsy; frequency-dependent facilitation; hippocampus; kainate receptor; mossy fiber; short-term plasticity; type II metabotropic glutamate receptor
Received Jan. 14, 2003; revised Mar. 26, 2003; accepted Apr. 9, 2003.
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