mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons

Miou Zhou, Weidong Li* (Corresponding Author), Shan Huang, Juan Song, Ju Young Kim, Xiaoli Tian, Eunchai Kang, Yoshitake Sano, Cindy Liu, J Balaji, Shumin Wu, Yu Zhou, Ying Zhou, Sherveen N Parivash, Dan Ehninger, Lin He, Hongjun Song, Guo-Li Ming, Alcino J Silva* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

84 Citations (Scopus)


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
Original languageEnglish
Pages (from-to)647-654
Number of pages8
Issue number4
Publication statusPublished - 20 Feb 2013
Externally publishedYes

Bibliographical note

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.


  • Aging
  • Animals
  • Cognition/physiology
  • Dentate Gyrus/cytology
  • Gene Knockdown Techniques
  • Mice
  • Nerve Tissue Proteins/genetics
  • Neurogenesis/genetics
  • Neurons/cytology
  • Signal Transduction/genetics
  • TOR Serine-Threonine Kinases/antagonists & inhibitors


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