ANTICONVULSANT EFFECT OF REDUCED NMDA RECEPTOR EXPRESSION IN AUDIOGENIC DBA 2 MICE/

Pretreatment of DBA/2 mice (n = 14-15 per group) with an 18-mer antise nse probe to the NMDA-receptor subunit NR1 (2 x 1 mu g, or 2 x 83 pmol , NR1 antisense probe intracerebroventricularly, -29 and -7 h before t esting for seizure response) resulted in almost complete suppression o f sound-induced clonic seizures. A saline-treated group gave a 100% se izure response, while the group treated with the NR1 antisense probe g ave a 7% seizure response to the sound stimulus. The group treated wit h the NR1 nonsense-probe showed no anticonvulsant protection (93% seiz ure response). The anticonvulsant protection observed following NR1 an tisense administration was of relatively short duration, with seizure response gradually returning to control levels 12 to 24 h following th e termination of antisense administration. When Mil receptor levels we re assessed by receptor autoradiography ([H-3]-MK 801 and [H-3]-CGP 39 653 binding) in the same groups of mice, significant (20%) reductions in NR1 levels were observed in the retrosplenial cortex and the overal l cortex. The seizure-induced expression of c-fos and NGFI-A in thalam us, hypothalamus, inferior colliculus and medial geniculate seen in ve hicle- and NR1 nonsense-treated mice was completely blocked by NR1 ant isense pretreatment.