TY - JOUR
T1 - mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons
AU - Zhou, Miou
AU - Li, Weidong
AU - Huang, Shan
AU - Song, Juan
AU - Kim, Ju Young
AU - Tian, Xiaoli
AU - Kang, Eunchai
AU - Sano, Yoshitake
AU - Liu, Cindy
AU - Balaji, J
AU - Wu, Shumin
AU - Zhou, Yu
AU - Zhou, Ying
AU - Parivash, Sherveen N
AU - Ehninger, Dan
AU - He, Lin
AU - Song, Hongjun
AU - Ming, Guo-Li
AU - Silva, Alcino J
N1 - Copyright © 2013 Elsevier Inc. All rights reserved.
We thank Denise Cai for help with statistical analysis, Yong-Seok Lee and Justin Shobe for helpful advice, and Tawnie Silva, Aida Amin, and Katie Cai for technical support. This work was supported by grants from the National Institutes of Mental Health (P50-MH0779720), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Staglin IMHRO Center for Cognitive Neuroscience at UCLA to A.J.S., National Institute of Health (NS048271, HD069184) and NARSAD Investigator Award to G.L.M., National Institute of Health (NS047344) to H.J.S., China 973 Program (2010CB529604), National Scientific Foundation of China (81271511, 30900432), National Science & Technology Pillar Program (2012BAI01B08,
Neuron Disc1 KD in Adult-Born Neurons Causes Deficits 2012BAI01B09), Shanghai Pujiang Program (11PJ1405100), ‘‘Eastern
Scholar,’’ ‘‘Shu Guang’’ project supported by Shanghai Municipal
Education Commission and Shanghai Education Development Foundation (10SG14), ‘‘National Major Scientific Instruments Development Project’’ (2012YQ03026007), and NARSAD Young Investigator Award to W.L., NSFC (NSFC31222027, NSFC3117107) and SD NSF (SDNSF JQ201209) to Y.Z., and NARSAD Young Investigator Awards to M.Z. M.Z., W.L., and A.J.S. designed the experiments. M.Z., S.H., and W.L. performed the behavioral
experiments. M.Z. did
immunostaining and data analysis. J.S. did eletrophysiological recording. E.K. carried out the axonal targeting experiment. J.Y.K.
provided the virus. H.S. and G.M. helped with paper writing. M.Z. and A.J.S. wrote the paper.
PY - 2013/2/20
Y1 - 2013/2/20
N2 - Abnormalities during brain development are thoughtto cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restrictedbrain regions of adults, and disruptions of theseprocesses could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specificallyin adult-born dentate gyrus (DG) neurons results inincreased mTOR signaling, hyperexcitability, andneuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits,which could be reversed when the affected DGneurons were inactivated. Importantly, reversingincreases in mTOR signaling with an FDA-approvedinhibitor both prevented and treated these behavioraldeficits, even when associated structural deficitswere not reversed. Our findings suggest thata component of the affective and cognitive phenotypes in neurodevelopmental disorders may becaused by disruptions in adult-born neurons. Consequently, treatments directed at this cell populationmay have a significant impact on these phenotypes
AB - Abnormalities during brain development are thoughtto cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restrictedbrain regions of adults, and disruptions of theseprocesses could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specificallyin adult-born dentate gyrus (DG) neurons results inincreased mTOR signaling, hyperexcitability, andneuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits,which could be reversed when the affected DGneurons were inactivated. Importantly, reversingincreases in mTOR signaling with an FDA-approvedinhibitor both prevented and treated these behavioraldeficits, even when associated structural deficitswere not reversed. Our findings suggest thata component of the affective and cognitive phenotypes in neurodevelopmental disorders may becaused by disruptions in adult-born neurons. Consequently, treatments directed at this cell populationmay have a significant impact on these phenotypes
KW - Aging
KW - Animals
KW - Cognition/physiology
KW - Dentate Gyrus/cytology
KW - Gene Knockdown Techniques
KW - Mice
KW - Nerve Tissue Proteins/genetics
KW - Neurogenesis/genetics
KW - Neurons/cytology
KW - Signal Transduction/genetics
KW - TOR Serine-Threonine Kinases/antagonists & inhibitors
U2 - 10.1016/j.neuron.2012.12.033
DO - 10.1016/j.neuron.2012.12.033
M3 - Article
C2 - 23439118
VL - 77
SP - 647
EP - 654
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 4
ER -