Reduction in delayed mortality and subtle improvement in retrograde memory performance in pilocarpine-treated mice with conditional neuronal deletion of cyclooxygenase-2 gene

Purpose: Pilocarpine induces prolonged status epilepticus (SE) in rodents that results in neurodegeneration and cognitive deficits, both commonly observed to be associated with human temporal lobe epilepsy. The multifunctional neuronal modulator, cyclooxygenase-2 (PTGS2 or COX-2), is rapidly induced after SE, mainly in principal neurons of the hippocampal formation and cortex. We used mice in which COX-2 is conditionally ablated in principal fore-brain neurons to investigate the involvement of neuronderived COX-2 in delayed mortality and performance in the Barnes maze. Methods: Using the COX-2 conditional knockout mouse (nCOX-2 cKO) and their littermate wild-type controls, we compared motor behavior and performance in the Barnes maze before and 3 weeks after the induction of SE by pilocarpine. Mortality rate was also measured during SE and in the week following SE. Key Findings: nCOX-2 cKO mice showed less delayed mortality than wild-type mice in the week after SE. Although motor behavior and most cognitive measures were not different in the nCOX-2 cKO, upon reexposure to the maze 3 weeks after pilocarpine, the latency to find the previously learned target hole was significantly shorter in the nCOX-2 cKO than their wild-type littermate controls. By this measure pilocarpine-treated nCOX-2 cKO mice were identical to mice that had not experienced SE. Significance: Results point to a role for neuronal COX-2 in delayed mortality in mice during the week following SE and suggest that neuronal COX-2 contributes to selected cognitive deficits observed after SE. Taking into consideration our previous findings that neurodegeneration and neuroinflammation after SE are reduced in the nCOX-2 cKO, and opening of the blood-brain barrier after pilocarpine is prevented, we conclude that neuronal COX-2 induction is an early step in many of the deleterious consequences of SE.