Pilocarpine-induced status epilepticus increases cell proliferation in the dentate gyrus of adult rats via a 5-HT 1A receptor-dependent mechanism

Abstract

The dentate gyrus continues to produce granule neurons throughout life. Mossy fibers, the axons of granule neurons, undergo atypical sprouting in both clinical and experimental mesial temporal lobe epilepsy. Mossy fiber sprouting (MFS) has been hypothesized to underlie the network reorganization that is thought to produce spontaneously recurring seizures, possibly via the formation of new recurrent excitatory circuits. Hippocampal neurogenesis may be a critical step in the development of MFS, given that it is enhanced by at least 2-fold in the aftermath of pilocarpine-induced status epilepticus. Since it is known that serotonin (5-HT) 1A receptor activation also increases granule cell genesis in the dentate gyrus in rats, and reciprocally, that blockade of this receptor decreases it, we examined whether 5-HT 1A receptor blockade would prevent the seizure-induced enhancement of neurogenesis. The ability to block seizure-induced neurogenesis would provide a test for its role in the network reorganization, especially in regards to MFS, which might underlie seizure development. In the present study, it was found that blockade of the 5-HT 1A receptor before and after pilocarpine treatment prevented seizure-induced hippocampal cell proliferation and survival, and, its prevention by chronic treatment with a 5-HT 1A receptor antagonist (WAY-100,635) did not prevent the development of MFS or spontaneously recurring seizures. Taken together, these results suggest that 5-HT 1A receptor activation is a critical step in the activation of seizure-induced cell proliferation and survival in the dentate gyrus, however, not for the onset of spontaneously recurrent seizures and MFS.