Status epilepticus causes long-term NMDA receptor-dependent behavioral changes and cognitive deficits.

Abstract

The role of N-methyl-D-aspartate (NMDA)-receptor activation on behavioral and cognitive changes after status epilepticus (SE) is unknown. In this study, behavioral and cognitive changes after SE were evaluated in the short and long term and in rats in which the NMDA receptor was inactivated during SE. Pilocarpine (350 mg/kg) was injected to induce SE. Inhibition of the NMDA receptor during SE was achieved with MK-801 (4 mg/kg). Seizure intensity during SE was monitored by electroencephalography (EEG). After SE, behavioral studies were performed to identify abnormal behavior by using behavioral tests adapted from Moser's functional observational battery. Cognitive changes were assessed by using the Morris Water Maze (MWM). Pilocarpine-treated animals scored significantly higher on two of the behavioral tests: the Touch test and the Pick-Up test. These behavioral changes occurred very soon after SE, with the earliest changes observed 2 days after SE and persisting for the life of the animal. Inhibition of the NMDA receptor with MK-801 completely inhibited these behavioral changes under conditions that did not alter the duration of SE. In addition, pilocarpine-treated animals exhibited cognitive deficits as determined by using the MWM. Six weeks after SE, the animals displayed significantly longer latencies to locate the hidden platform on this test. The impaired performance on the MWM also occurred as early as 5 days after SE. These cognitive deficits were prevented in animals treated with MK-801 during SE. The results indicate that behavioral and cognitive changes occur soon after SE, are permanent, and are dependent on NMDA-receptor activation during SE. NMDA-receptor activation may play an important role in causing cognitive and behavioral morbidity after recovery from SE.