Title:
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Methylphenidate attenuates the cognitive and mood alterations observed in mbnl2 knockout mice and reduces mcroglia overexpression
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Author:
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Ramon-Duaso, Carla; Gener, Thomas; Consegal, Marta; Fernández-Avilés, Cristina; Gallego, Juan José; Castarlenas, Laura; Swanson, Maurice S.; Torre Fornell, Rafael de la; Maldonado, Rafael, 1961-; Puig Velasco, María Victoria; Robledo, Patricia, 1958-
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Abstract:
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Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting muscle and central nervous system (CNS) function. The cellular mechanisms underlying CNS alterations are poorly understood and no useful treatments exist for the neuropsychological deficits observed in DM1 patients. We investigated the progression of behavioral deficits present in male and female muscleblind-like 2 (Mbnl2) knockout (KO) mice, a rodent model of CNS alterations in DM1, and determined the biochemical and electrophysiological correlates in medial prefrontal cortex (mPFC), striatum and hippocampus (HPC). Male KO exhibited more cognitive impairment and depressive-like behavior than female KO mice. In the mPFC, KO mice showed an overexpression of proinflammatory microglia, increased transcriptional levels of Dat, Drd1, and Drd2, exacerbated dopamine levels, and abnormal neural spiking and oscillatory activities in the mPFC and HPC. Chronic treatment with methylphenidate (MPH) (1 and 3 mg/kg) reversed the behavioral deficits, reduced proinflammatory microglia in the mPFC, normalized prefrontal Dat and Drd2 gene expression, and increased Bdnf and Nrf2 mRNA levels. These findings unravel the mechanisms underlying the beneficial effects of MPH on cognitive deficits and depressive-like behaviors observed in Mbnl2 KO mice, and suggest that MPH could be a potential candidate to treat the CNS deficiencies in DM1 patients. |
Abstract:
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Fundació la Marató de TV3 (231/C/2014), and Instituto de Salud Carlos III (PI14/00210) to P.R.; Agency for Management of University and Research Grants (AGAUR) (ICREA Acadèmia-2015), AGAUR (SGR2009-00731), Ministerio de Economía Industria y Competitividad (MINECO) (SAF2014-59648-P), and Instituto de Salud Carlos III-RETICS/RTA (RD16/0017/0020) to R.M.; MINECO (SAF2016-80726-R) to M.V.P.; and AGAUR (SGR2014-680) to R.T.F. |
Subject(s):
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-Miotonia atròfica -Dopamina -Metilfenidat -Micròglia |
Rights:
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info:eu-repo/semantics/embargoedAccess
© Oxford University Press. This is a pre-copyedited, author-produced version of an article accepted for publication in Cerebral Cortex following peer review. The version of record Ramon-Duaso C, Gener T, Consegal M, Fernández-Avilés C, Gallego JJ, Castarlenas L. Methylphenidate attenuates the cognitive and mood alterations observed in mbnl2 knockout mice and reduces mcroglia overexpression. Cereb Cortex. 2018 Jul 27. [Epub ahead of print] is available online at: http://doi.org/10.1093/cercor/bhy164 |
Document type:
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Article Article - Accepted version |
Published by:
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Oxford University Press
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