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Reduced spatial learning in mice treated with NVP-AAM077 through down-regulating neurogenesis

Hu, Mei and Sun, Yong-Jun and Zhou, Qi-Gang and Auberson, Yves and Chen, Ling and Hu, Yao and Luo, Chun-Xia and Wu, Jia-Yi and Zhu, Dong-Ya and Li, Li-Xin (2009) Reduced spatial learning in mice treated with NVP-AAM077 through down-regulating neurogenesis. European Journal of Pharmacology, 622 (1-3). pp. 37-44. ISSN 00142999

Abstract

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 NR2Acontaining
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 hippocampalmediated
learning. To explore the possible mechanisms understanding the reduced spatial memory by NVPAAM077,
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.

Item Type: Article
Keywords: NVP-AAM077; NR2A; Spatial memory; Neurogenesis; nNOS
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2994

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