Abstracts

RATIONALE: Understanding the mechanisms underlying epileptogenesis is crucial for new therapy development. The association between mossy fiber sprouting (mfs) and an epileptic phenotype has led to the idea that formation of recurrent excitatory synapses between granule cells coincident with mfs contributes to limbic epileptogenesis.
METHODS: To begin to test this idea, organotypic hippocampal slice cultures were treated chronically with drugs shown previously to induce (tetrodotoxin, TTX) or inhibit (D-APV) epileptogenesis. Electrographic granule cell seizures were recorded extracellularly and mfs was assessed with Timm stain.
RESULTS: -treated slice cultures exhibited a progressive increase in seizure incidence as a function of time in culture in response to GABA[sub]A [/sub] receptor blockade with bicuculline (BMI); 0% of cultures at [lt]5 DIV, 67% at 10-13 DIV, 100% at [gt] 17 DIV. No spontaneous seizures were seen in 3-21 DIV cultures in physiological buffer (ACSF) and minimal mfs was noted. In contrast, 83% of 17-21 DIV -treated cultures exhibited seizures during TTX washout in ACSF and robust mfs was noted. In 17-21 DIV -treated cultures, seizure incidence was not altered but BMI-induced seizure duration was increased. Moderate mfs was noted.
CONCLUSIONS: These data suggest that D-APV does not inhibit epileptogenesis in our [italic]in vitro[/italic] model and treatments that exacerbate seizures also increase mfs.
Support: the American Epilepsy Society with support from the Milken Family Foundation, USUHS protocol CO75HK (SBB), NIH grants NS17771, NS32334 (JOM)