Abstracts

Rationale: Patients with temporal lobe epilepsy display many pathological changes in the dentate gyrus, including hilar neuron loss, granule cell axon (mossy fiber) sprouting, GABAergic axon sprouting, ectopic hilar granule cells, and others. It is unclear which of these circuit anomalies, if any, contribute to epileptogenesis. To address that issue, one would like to selectively block specific changes and identify those that affect development of spontaneous seizures. Recent evidence suggests the mTOR inhibitor, rapamycin, might be useful in this regard. Methods: GIN mice, which express GFP in a subset of somatostatin interneurons, were treated with pilocarpine to induce status epilepticus. Beginning 1 d later, mice were treated daily with rapamycin (3 mg/kg, ip). To evaluate epileptogenesis, mice were video-monitored daily 9 h/d during the second month after pilocarpine-induced status epilepticus. To more rigorously evaluate epileptogenesis, mice were video-EEG monitored with an electrode implanted in the hippocampus. Recordings were obtained daily 9 h/d during the third month after status epilepticus. Results: After 2 months, rapamycin-treated mice displayed less mossy fiber and less GFP-positive axon sprouting in the granule cell layer molecular layer compared to vehicle-treated controls. Hilar neuron loss, number of granule cells, and number of Prox1-immunoreactive hilar ectopic granule cells was similar in rapamycin- and vehicle-treated epileptic mice. The frequency and severity of seizures was similar in rapamycin- and vehicle-treated mice. Conclusions: One interpretation of these data is that axon sprouting in the dentate gyrus is not epileptogenic but hilar neuron loss and generation of ectopic granule cells might be. However, mossy fiber and somatostatin axon sprouting might have opposing effects, and rapamycin might affect epileptogenesis through other mechanisms that were not evaluated in the present study. Nevertheless, these findings suggest that targeting signal transduction mechanisms is a useful strategy to more selectively test the epileptogenicity of circuit changes in temporal lobe epilepsy. Supported by NIH (NINDS/NCRR)