Long-lasting disruption of spatial memory by GABAB receptor antagonist induced seizures

Abstract

The objective of this project was to test whether a drug-induced model of temporal lobe seizures, namely seizures induced by a gamma aminobutyric acid (GABAB) receptor antagonist, CGP35348, result in long-term disruption of hippocampal memory function. Seizures were induced in experimental rats by intracerebroventricular (i.c.v.) injection of CGP35348 (0.64 μmol in 3 μL) for three consecutive days; control rats received no injection. Rats were first trained to criterion on an open radial arm maze (RAM) with 4 of the 8 arms baited, then received seizure and control treatment, and tested again on the RAM during the first week (days 1–5) and fourth week (days 22–29) after the last injection. An initial i.c.v. CGP35348 injection induced a mean of 4.4 seizures in the hippocampus, often accompanied with stages 3–5 convulsions, and sometimes with jumping; three daily CGP35348 injections induced 10.4 ± 1.8 (n = 7 rats) seizures in total. In two separate experiments, seizure-treated rats performed worse than control rats in working memory (WM) during both the 1st and 4th weeks after seizures. Reference memory (RM) deficit during the 1st week after seizures was observed in only one experiment in which RM was acquired >2 weeks ago. The memory deficits were not accompanied by gross neuronal loss in the hippocampus. In conclusion, i.c.v. injection of a GABAB receptor antagonist in adult rats induced brief, multiple, focal hippocampal seizures that induced deficits in spatial memory for up to 4 weeks.