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 antisense probe to the NMDA-receptor submit NR1 (2 x 1 micrograms, or 2 x 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% seizures response, while the group treated with NR1 antisense probe gave a 7% seizure response to the sound stimulus. The group treated with 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 ([3H]-MK 801 and -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 medical geniculate seen in vehicle- and NR1 nonsense-treated mice was completely blocked by NR1 antisense pretreatment.
Chapman
A G
AG
Department of Neurology, Institute of Psychiatry, London, UK.
Woodburn
V L
VL
Woodruff
G N
GN
Meldrum
B S
BS
D000161:Acoustic Stimulation; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000502:physiology; D001345:Autoradiography; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology*; D018389:Codon, Nonsense / Q000502:physiology; D016291:Dizocilpine Maleate / Q000378:metabolism; D005260:Female; D017781:Genes, Immediate-Early / Q000235:genetics / Q000502:physiology; D007245:Inferior Colliculi / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D012640:Seizures / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*
D016375:Antisense Elements (Genetics); D018389:Codon, Nonsense; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate