Methylphenidate Attenuates the Cognitive and Mood Alterations Observed in<i>Mbnl2</i>Knockout Mice and Reduces Microglia Overexpression

  • Carla Ramon-Duaso
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • Thomas Gener
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • Marta Consegal
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • Cristina Fernández-Avilés
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • Juan José Gallego
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • Laura Castarlenas
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • Maurice S Swanson
    Department of Molecular Genetics and Microbiology and the Center for NeuroGenetics, University of Florida, College of Medicine, Gainesville, FL, USA
  • Rafael de la Torre
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • Rafael Maldonado
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • M Victoria Puig
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
  • Patricia Robledo
    Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Research Institute, Barcelona, Spain

抄録

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

収録刊行物

  • Cerebral Cortex

    Cerebral Cortex 29 (7), 2978-2997, 2018-07-27

    Oxford University Press (OUP)

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