Abstracts

Rationale: Severe temporal lobe epilepsy (TLE) may be associated with neurological damage including neuronal cell death, hippocampal sclerosis, aberrant neurogenesis, and mossy fiber sprouting. Severe seizures may lead to the rapid loss of hippocampal GABAergic interneurons, which are particularly vulnerable to excitotoxic damage. The resulting imbalance in the ratio of excitation to inhibition in hippocampal circuits is hypothesized to be a leading cause of epileptogenesis. Efforts to prevent the loss of GABAergic interneurons have not yet been successful, however some prior studies suggest that the neurotransmitter serotonin (5-HT) may be neuroprotective for hippocampal neurons. Here we have tested whether augmenting serotonin signaling is neuroprotective in a mouse model of temporal lobe epilepsy. Methods: To test whether augmenting 5-HT is neuroprotective in mice, we injected 5-carboxyamidotryptamine (5-CT), an agonist for 5-HT1A and 5-HT7 receptors into adult male C57Bl/6HSD mice 24 hours before inducing status epilepticus (SE) with systemic pilocarpine. The severity of the seizures was evaluated in 5CT-treated vs. control mice by counting the latency to reach status epilepticus and number of seizure events before reaching SE. We assessed neurodegeneration in the CA1 subfield and the hilus in non-adjacent cryostat sections of the anterior hippocampus several hours after the onset of SE, by Fluoro Jade B, a histological stain for acute neurodegeneration. Results: Our results show that 5-CT activation of 5-HT1A and 5-HT7 receptors increased the number of seizure events required for reaching SE, but compared with controls, 5-CT-treated mice also experienced higher mortality rates. Mice treated with 5-CT and 5-HT1A antagonist WAY-100 had mortality rates and SE thresholds that were in between the other groups. In control mice, neurodegeneration in CA1 and hilar regions of the hippocampus was severe following SE (average of 237.0 +/- 40.3 degenerating neurons). The most neuroprotection was observed in the 5-CT treated mice (139.4 +/- 37.9 degenerating neurons), which was a statistically significant reduction in cell death compared with control mice (p=0.004). An intermediate level of cell death was observed in the group of mice treated with both 5-CT + WAY-100 (197.4 +/- 69.8 degenerating neurons). This level of neurodegeneration was not significantly different from either the controls or the 5-CT treated group. Conclusions: These data suggest that activation of serotonin receptors with 5-CT prior to seizure events is an effective neuroprotective treatment that reduces interneuron death following Status Epilepticus in mice. Further studies are required to establish the molecular mechanism for the observed neuroprotection and to determine whether interneuron death is prevented or merely delayed.