Anticonvulsant effect of reduced NMDA receptor expression in audiogenic DBA/2 mice

Abstract Pretreatment of DBA/2 mice ( n = 14–15 per group) with an 18-mer antisense probe to the NMDA-receptor subunit NR1 (2 × 1 μg, or 2 × 83 pmol, NR1 antisense probe intracerebroventricularly, −29 and −7 h before testing for seizure response) resulted in almost complete suppression of sound-induced clonic seizures. A saline-treated group gave a 100% seizure response, while the group treated with the NR1 antisense probe gave a 7% seizure response to the sound stimulus. The group treated with the NR1 nonsense-probe showed no anticonvulsant protection (93% seizure response). The anticonvulsant protection observed following NR1 antisense administration was of relatively short duration, with seizure response gradually returning to control levels 12 to 24 h following the termination of antisense administration. When NR1 receptor levels were assessed by receptor autoradiography ([ 3 H]-MK 801 and [ 3 H]-CGP 39653 binding) in the same groups of mice, significant (20%) reductions in NR1 levels were observed in the retrosplenial cortex and the overall cortex. The seizure-induced expression of c- fos and NGFI-A in thalamus, hypothalamus, inferior colliculus and medial geniculate seen in vehicle- and NR1 nonsense-treated mice was completely blocked by NR1 antisense pretreatment.