Antisense hippocampal knockdown of NMDA-NR1 by HVJ-liposome vector induces deficit of prepulse inhibition but not of spatial memory.
Considerable evidence suggests that an N-methyl-D-aspartate (NMDA) receptor plays a crucial role in memory and cognitive function. To identify the role of this receptor in higher functions of the brain, we delivered antisense oligonucleotides against an NMDA-NR1 subunit (NR1) to the hippocampus in rats using the HVJ-liposome-mediated gene-transfer method. NR1 hippocampal knockdown was performed by the focal injection of the NR1 antisense-HVJ-liposome complex into the bilateral hippocampus. The blocking effect of NR1-antisense on the expression of NR1 was confirmed by Western blot analysis. Spatial memory was tested by a water maze task, and sensorimotor gating was examined by prepulse inhibition (PPI). Western blot analysis demonstrated that the NR1-antisense treatment specifically provided the down-regulation (about 30%) of NR1 protein levels in the hippocampus. The water maze task showed that the antisense treatment did not affect spatial memory, while the PPI test revealed that NR1 hippocampal knockdown caused a deficit in sensorimotor gating. We conclude that mild dysfunction of hippocampal NMDA receptor causes sensorimotor gating deficit and relatively intact in spatial memory.
Inada
Ken
K
Department of Psychiatry, School of Medicine, Kitasato University, Sagamihara, Kanagawa 228-8520, Japan. byi00425@nifty.com
Ishigooka
Jun
J
Anzai
Takeshi
T
Suzuki
Eiji
E
Miyaoka
Hitoshi
H
Saji
Makoto
M
D000818:Animals; D030801:Animals, Genetically Modified; D015536:Down-Regulation; D018014:Gene Transfer Techniques; D022761:Gene Transfer, Horizontal; D005822:Genetic Vectors; D006624:Hippocampus / Q000502:physiology*; D007276:Injections, Intraventricular; D008081:Liposomes; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D029082:Sendai virus / Q000235:genetics; D013873:Thionucleotides / Q000235:genetics
D008081:Liposomes; D016376:Oligonucleotides, Antisense; D016194:Receptors, N-Methyl-D-Aspartate; D013873:Thionucleotides