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Reelin Improves Cognition and Extends the Lifespan of Mutant Ndel1 Mice with Postnatal CA1 Hippocampus Deterioration

Kiroski, Ivana and Jiang, Yulan and Gavrilovici, Cezar and Gao, Fan and Lee, Sukyoung and Scantlebury, Morris H. and Vandal, Milene and Park, Sang Ki and Tsai, Li-Huei and Teskey, G. Campbell and Rho, Jong M. and Nguyen, Minh Dang (2020) Reelin Improves Cognition and Extends the Lifespan of Mutant Ndel1 Mice with Postnatal CA1 Hippocampus Deterioration. Cerebral Cortex . ISSN 1047-3211. (In Press)

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The glycoprotein Reelin maintains neuronal positioning and regulates neuronal plasticity in the adult brain. Reelin deficiency has been associated with neurological diseases. We recently showed that Reelin is depleted in mice with a targeted disruption of the Ndel1 gene in forebrain postnatal excitatory neurons (Ndel1 conditional knockout (CKO)). Ndel1 CKO mice exhibit fragmented microtubules in CA1 pyramidal neurons, profound deterioration of the CA1 hippocampus and a shortened lifespan (~10 weeks). Here we report that Ndel1 CKO mice (of both sexes) experience spatial learning and memory deficits that are associated with deregulation of neuronal cell adhesion, plasticity and neurotransmission genes, as assessed by genome-wide transcriptome analysis of the hippocampus. Importantly, a single injection of Reelin protein in the hippocampus of Ndel1 CKO mice improves spatial learning and memory function and this is correlated with reduced intrinsic hyperexcitability of CA1 pyramidal neurons, and normalized gene deregulation in the hippocampus. Strikingly, when treated with Reelin, Ndel1 CKO animals that die from an epileptic phenotype, live twice as long as nontreated, or vehicle-treated CKO animals. Thus, Reelin confers striking beneficial effects in the CA1 hippocampus, and at both behavioral and organismal levels.

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Additional Information:© The Author(s) 2020. Published by Oxford University Press. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model ( Received: 11 December 2019; Revision received: 25 February 2020; Accepted: 21 March 2020; Published: 24 April 2020. We are grateful to Dr Tom Curran and Dr Joachim Herz for the Reelin-expressing cell line. The Canadian Institutes of Health Research (CIHR; MOP74624 and MOP130495 to M.D.N. and G.C.T.); Alberta Innovates Health Solutions (AIHS) (to M.D.N.); the Alberta Children’s Hospital Research Institute (to C.G. and J.M.R.); CIHR and a AIHS postdoctoral scholarship (to M.V.); Donald Burns and Louise Berlin graduate scholarship from the Hotchkiss Brain Institute (to S.L.). This work was also supported by the Brain Research Program (2015M3C7A1030964 and 2017M3C7A1047875) funded by Korean National Research Foundation (KNRF) (to S.K.P).
Funding AgencyGrant Number
Canadian Institutes of Health Research (CIHR)MOP74624
Canadian Institutes of Health Research (CIHR)MOP130495
Alberta Innovates Health SolutionsUNSPECIFIED
Alberta Children’s Hospital Research InstituteUNSPECIFIED
Hotchkiss Brain InstituteUNSPECIFIED
National Research Foundation of Korea2015M3C7A1030964
National Research Foundation of Korea2017M3C7A1047875
Record Number:CaltechAUTHORS:20200522-124105657
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Official Citation:Ivana Kiroski, Yulan Jiang, Cezar Gavrilovici, Fan Gao, Sukyoung Lee, Morris H Scantlebury, Milene Vandal, Sang Ki Park, Li-Huei Tsai, G Campbell Teskey, Jong M Rho, Minh Dang Nguyen, Reelin Improves Cognition and Extends the Lifespan of Mutant Ndel1 Mice with Postnatal CA1 Hippocampus Deterioration, Cerebral Cortex, bhaa088,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103420
Deposited By: Tony Diaz
Deposited On:22 May 2020 20:43
Last Modified:22 May 2020 20:43

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