Up-regulation of d-serine Might Induce GABAergic Neuronal Degeneration in the Cerebral Cortex and Hippocampus in the Mouse Pilocarpine Model of Epilepsy

Epilepsy is a serious neurological disorder with neuronal loss and spontaneous recurrent seizures, but the neurochemical basis remains largely unclear. We hypothesize that d-serine, a newly identified endogenous co-agonist of N-methyl-d-aspartate (NMDA) receptor, may trigger excitotoxicity and neuronal damage in epileptogenesis. By using a mouse pilocarpine model, immunohistochemistry, Fluoro-Jade staining and double-labeling, the present study revealed up-regulation of d-serine expression in a proportion (41%) of neurons in the cerebral cortex and hippocampus. The d-serine-positive neurons occurred at 4 h, reached peak levels at 12-24 h, and gradually went down at 3-14 days. Moreover, most of d-serine-positive neurons were GABAergic (98%), underwent degenerating death (93%), and were accompanied enhancing phosphorylation of NMDA receptor subunit 1. This study has provided new evidence that up-regulation of d-serine production might induce GABAergic neuronal degeneration through excitotoxic mechanism in the pilocarpine model and may be involved in early pathogenesis and recurrent seizure of chronic epilepsy.