Reduced spatial learning in mice treated with NVP-AAM077 through down-regulating neurogenesis.
NR2A-containing N-methyl-D-aspartate (NMDA) receptors have important roles in influencing the long-term potentiation and spatial memory. Here using Morris water maze, we found that inhibition of NR2A-containing NMDA receptors by [(R)-[(S)-1-(4-bromophenyl)-ethylamino]-(2, 3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) hindered the formation of spatial memory. An increasing number of reports suggest that adult hippocampal neurogenesis is involved in hippocampal-mediated learning. To explore the possible mechanisms understanding the reduced spatial memory by NVP-AAM077, we investigated the effects of NVP-AAM077 on neurogenesis. We found that NVP-AAM077 inhibited progenitor cells proliferation in the subventricular zone and dentate gyrus and reduced the survival of newborn cells in the dentate gyrus in the adult mice. In null mutant mice lacking neuronal nitric oxide synthase (nNOS) gene (nNOS(-/-)), the effects of NVP-AAM077 on neurogenesis disappeared. In addition, NVP-AAM077 increased nNOS enzymatic activity. Our findings suggest that NVP-AAM077 reduced spatial learning through down-regulating neurogenesis in the adult hippocampus.
Hu
Mei
M
Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
Sun
Yong-Jun
YJ
Zhou
Qi-Gang
QG
Auberson
Yves P
YP
Chen
Ling
L
Hu
Yao
Y
Luo
Chun-Xia
CX
Wu
Jia-Yi
JY
Zhu
Dong-Ya
DY
Li
Li-Xin
LX
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002552:Cerebral Ventricles / Q000166:cytology; D018891:Dentate Gyrus / Q000166:cytology; D007858:Learning / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013379:Substrate Specificity
D052248:Nitric Oxide Synthase Type I; D021122:Protein Subunits; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione