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RVG-Mediated Calpain2 Gene Silencing in the Brain Impairs Learning and Memory

Zadran, Sohila and Akopian, Garnik and Zadran, Homera and Walsh, John and Baudry, Michel (2013) RVG-Mediated Calpain2 Gene Silencing in the Brain Impairs Learning and Memory. NeuroMolecular Medicine, 15 (1). pp. 74-81. ISSN 1535-1084.

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In the central nervous system, two calpain isoforms are highly expressed: calpain1 and calpain2. Here, we show for the first time that activation of the calpain isoform, calpain2, is a necessary event in hippocampal synaptic plasticity and in learning and memory. We developed a fluorescence resonance energy transfer–based animal model to monitor in vivo calpain activation in single cells and in real time. Additionally, utilizing a novel rabies virus glycoprotein-chimeric peptide, which enabled the transvascular delivery of small interfering RNA to the brain against calpain2, we down-regulated the calpain2 isoform in vivo. Calpain2 gene silencing eliminated long-term potentiation and impaired learning and memory. Our results not only identify the calpain2 isoform as a critical mediator in learning and memory but also highlight an innovative, highly efficient calpain2-targeting peptide capable of isoform-specific gene silencing in the brain. We anticipate these innovative technologies and our better understanding of the calpain machinery, particularly of the calpain2 isoform, will have substantial influence on future translational studies, attracting considerable interest in the use of calpain models and calpain-specific inhibitors in the development of therapeutics.

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Additional Information:© 2012 Springer Science+Business Media, LLC. Received: 10 July 2012; Accepted: 3 August 2012; Published online: 19 August 2012. We would like to express our gratitude to Drs. Haijiang Cai, Qingyu Qin and Xiaoning Bi for providing assistance in imaging and electrophysiology experiments. We are also grateful to Ariana Chehrazi, Georgina Smith, Lauren Alderette, James Bowman III and Maria Agosto for technical assistance. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (USC NINDS 5R01NS057128-03 to Dr. M Baudry). Dr. Sohila Zadran was supported by a National Institute of Health T32 Post-Doctoral Fellowship (Caltech NIH 5 T32NS7251-24 to Dr. R Andersen). Homera Zadran was supported by the National Science Foundation Graduate Research Fellowship Program (NSF GRFP).
Funding AgencyGrant Number
National Institute of Neurological Disorders and Stroke (NINDS)5R01NS057128-03
NIH5 T32NS7251-24
NSF Graduate Research Fellowship Program (GRFP)UNSPECIFIED
Subject Keywords:Calpain; Synaptic plasticity; Rabies virus glycoprotein; Learning and memory
Issue or Number:1
Record Number:CaltechAUTHORS:20130401-101040841
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37700
Deposited By: Tony Diaz
Deposited On:08 Apr 2013 22:19
Last Modified:03 Oct 2019 04:50

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