Abstracts

RATIONALE: Hippocampal sensitization underlying activity-dependent plasticity is likely to play an important role in epileptogenesis. While detailed mechanisms that underlie hippocampal sensitization are not fully understood, however several studies have implicated tachykinin-mediated events. We set out the hypothesis that activation of NK3 receptors (NK3R) in the hippocampus might modulate hippocampal sensitization associated with seizures. METHODS: Self-sustaining status epilepticus (SSSE) was induced by perforant path stimulation (PPS) for 30 min. Neurokinin B (NKB), senktide, and fluo-NKB were injected into the dentate gyrus (DG) of awake rats. NK3R antagonists, SR-142801 or L-769923 were injected into the DG of awake rats 5 min before the beginning or 10 min after the end of 30 min PPS. After the appropriate survival time, the rats were sacrificed by decapitation. Cryostat sections were incubated with 20 nM fluo-NKB at 40C for 2 h. RESULTS: SSSE resulted in NKB release from hippocampus and stimulated endocytosis of NK3R in the principle neurons and hilar neurons. These responses were dose-dependently prevented by injection of NK3R antagonists (1-200 nmol). Administration of either 1 nmol NKB or 10 nmol senktide induced seizures lasting 2-3 h. Selective NK3R antagonists completely blocked both the initiation and maintenance phase of SSSE induced by 30 min PPS. Injection of 0.5 nmol fluo-NKB, which caused seizures resembling those that occurred after injection of native NKB, induced trafficking of NKB/NK3R from the plasma membrane to the cytosol of hippocampal neurons. These effects were blocked by co-injection of 50 nmol SR-142801 and 0.5 nmol fluo-NKB. CONCLUSIONS: Our results show that NKB, via an action on NK3R, enhances excitability of the hippocampal neurons, and suggests that alterations of NKB and NK3R are a novel mechanism for generating hippocampal sensitization contributing to limbic seizures. Supported by NS13515 and the VA Research Service (C.G.W)