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

Miou Zhou; Weidong Li; 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

doi:10.1016/j.neuron.2012.12.033

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 journal › Article › peer-review

84 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	647-654
Number of pages	8
Journal	Neuron
Volume	77
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2012.12.033
Publication status	Published - 20 Feb 2013
Externally published	Yes

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.

Keywords

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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Cite this

Zhou, M., Li, W., Huang, S., Song, J., Kim, J. Y., Tian, X., Kang, E., Sano, Y., Liu, C., Balaji, J., Wu, S., Zhou, Y., Zhou, Y., Parivash, S. N., Ehninger, D., He, L., Song, H., Ming, G.-L., & Silva, A. J. (2013). mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons. Neuron, 77(4), 647-654. https://doi.org/10.1016/j.neuron.2012.12.033

Zhou, M, Li, W, Huang, S, Song, J, Kim, JY, Tian, X, Kang, E, Sano, Y, Liu, C, Balaji, J, Wu, S, Zhou, Y, Zhou, Y, Parivash, SN, Ehninger, D, He, L, Song, H, Ming, G-L & Silva, AJ 2013, 'mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons', Neuron, vol. 77, no. 4, pp. 647-654. https://doi.org/10.1016/j.neuron.2012.12.033

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

abstract = "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",

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author = "Miou Zhou and Weidong Li and Shan Huang and Juan Song and Kim, {Ju Young} and Xiaoli Tian and Eunchai Kang and Yoshitake Sano and Cindy Liu and J Balaji and Shumin Wu and Yu Zhou and Ying Zhou and Parivash, {Sherveen N} and Dan Ehninger and Lin He and Hongjun Song and Guo-Li Ming and Silva, {Alcino J}",

note = "Copyright {\textcopyright} 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), {\textquoteleft}{\textquoteleft}Eastern Scholar,{\textquoteright}{\textquoteright} {\textquoteleft}{\textquoteleft}Shu Guang{\textquoteright}{\textquoteright} project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (10SG14), {\textquoteleft}{\textquoteleft}National Major Scientific Instruments Development Project{\textquoteright}{\textquoteright} (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.",

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doi = "10.1016/j.neuron.2012.12.033",

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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

SN - 0896-6273

VL - 77

SP - 647

EP - 654

JO - Neuron

JF - Neuron

IS - 4

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

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Cite this