Glucocorticoid Receptor Activation Restores Learning Memory by Modulating Hippocampal Plasticity in a Mouse Model of Bra
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Glucocorticoid Receptor Activation Restores Learning Memory by Modulating Hippocampal Plasticity in a Mouse Model of Brain Vitamin B12 Deficiency Natacha Dreumont 1 & Khalid Mimoun 1 & Carine Pourié 1 & Edward V. Quadros 2 & Jean-Marc Alberto 1 Rémy Umoret 1 & Déborah Helle 1 & Aurélie Robert 1 & Jean-Luc Daval 1 & Jean-Louis Guéant 1 & Grégory Pourié 1,3
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Received: 21 March 2020 / Accepted: 7 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Cobalamin (Cbl, vitamin B12) deficiency or inborn errors of Cbl metabolism can produce neurologic disorders resistant to therapies, including cognitive dysfunction, mild mental retardation, memory impairment, and confusion. We used Cd320 KO mouse as a model for studying the pathological mechanisms of these disorders. Cd320 encodes the receptor (TCblR) needed for the cellular uptake of Cbl in the brain. The Cd320−/− mouse model presented an impaired learning memory that could be alleviated by a moderate stress, which produced also a greater increase of plasma corticosterone, compared to wild type animals. The present study investigated such a putative rescue mechanism in Cbl-deficient mice. At the molecular level in the brain of Cd320−/− mouse, the decreased methylation status led to a downregulation of glucocorticoid nuclear receptor (GR)/PPAR-gamma co-activator-1 alpha (PGC-1α) pathway. This was evidenced by the decreased expression of GR, decreased methylation of GR and PGC1α, and decreased dimerization and interaction of GR with PGC1α. This led to altered synaptic activity evidenced by decreased interaction between the NMDA glutamatergic receptor and the PSD95 post-synaptic protein and a lower expression of Egr-1 and synapsin 1, in Cd320−/− mice compared to the wild type animals. Intraperitonealinjectionofhydrocortisonerescuedthesemolecularchangesandnormalizedthelearningmemorytests. Ourstudy suggests adaptive influences of moderate stress on loss of memory and cognition due to brain Cbl deficiency. The GR pathway could be a potential target for innovative therapy of cognitive manifestations in patients with poor response to conventional Cbl treatment. Keywords Vitamin B12 . Cognition . Behavior . Signal transduction . Synapse
Introduction Vitamin B12 (cobalamin, Cbl) deficiency is associated with accelerated cognitive decline, abnormal brain aging, and Natacha Dreumont, Khalid Mimoun, Jean-Louis Guéant and Grégory Pourié contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02163-2) contains supplementary material, which is available to authorized users. * Grégory Pourié [email protected] 1
Université de Lorraine, INSERM U1256, NGERE, F-54000 Nancy, France
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SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
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NGERE, INSERM U1256, Faculté de Médecine, 9 avenue de la forêt de Haye, BP 50184, 54505 Vandoeuvre Les Nancy CEDEX, France
dementia [1–5]. Inherited disorders of cellular Cbl metabolism also lea
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