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Male-Specific cAMP Signaling in the Hippocampus Controls Spatial Memory Deficits in a Mouse Model of Autism and Intellectual Disability

  • Author Footnotes
    1 MZ and AM contributed equally to this work.
    Marta Zamarbide
    Footnotes
    1 MZ and AM contributed equally to this work.
    Affiliations
    Institute for Neuroscience and Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC
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  • Author Footnotes
    1 MZ and AM contributed equally to this work.
    Adele Mossa
    Footnotes
    1 MZ and AM contributed equally to this work.
    Affiliations
    Institute for Neuroscience and Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC
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  • Pablo Muñoz-Llancao
    Affiliations
    Institute for Neuroscience and Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC
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  • Molly K. Wilkinson
    Affiliations
    Institute for Neuroscience and Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC
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  • Heather L. Pond
    Affiliations
    Institute for Neuroscience and Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC
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  • Adam W. Oaks
    Affiliations
    Institute for Neuroscience and Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC
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  • M. Chiara Manzini
    Correspondence
    Address correspondence to M. Chiara Manzini, Ph.D.,The George Washington University, 2300 Eye Street NW, Ross Hall 650, Washington, DC 20037.
    Affiliations
    Institute for Neuroscience and Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC
    Search for articles by this author
  • Author Footnotes
    1 MZ and AM contributed equally to this work.
Published:December 27, 2018DOI:https://doi.org/10.1016/j.biopsych.2018.12.013

      Abstract

      Background

      The prevalence of neurodevelopmental disorders is biased toward male individuals, with male-to-female ratios of 2:1 in intellectual disability and 4:1 in autism spectrum disorder. However, the molecular mechanisms of such bias remain unknown. While characterizing a mouse model for loss of the signaling scaffold coiled-coil and C2 domain-containing protein 1A (CC2D1A), which is mutated in intellectual disability and autism spectrum disorder, we identified biochemical and behavioral differences between male and female mice, and explored whether CC2D1A controls male-specific intracellular signaling.

      Methods

      CC2D1A is known to regulate phosphodiesterase 4D (PDE4D), which regulates cyclic adenosine monophosphate (cAMP) signaling. We tested for activation of PDE4D and downstream signaling molecules in the hippocampus of Cc2d1a-deficient mice. We then performed behavioral studies in female mice to analyze learning and memory, and then targeted PDE4D activation with a PDE4D inhibitor to define how changes in cAMP levels affect behavior in male and female mice.

      Results

      We found that in Cc2d1a-deficient male mice PDE4D is hyperactive, leading to a reduction in cAMP response element binding protein signaling, but this molecular deficit is not present in female mice. Cc2d1a-deficient male mice show a deficit in spatial memory, which is not present in Cc2d1a-deficient female mice. Restoring PDE4D activity using an inhibitor rescues cognitive deficits in male mice but has no effect on female mice.

      Conclusions

      Our findings show that CC2D1A regulates cAMP intracellular signaling in a male-specific manner in the hippocampus, leading to male-specific cognitive deficits. We propose that male-specific signaling mechanisms are involved in establishing sex bias in neurodevelopmental disorders.

      Keywords

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