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Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1

  • Author Footnotes
    1 Authors GDS and EP contributed equally to this work.
    Grazia Della Sala
    Footnotes
    1 Authors GDS and EP contributed equally to this work.
    Affiliations
    Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence
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  • Author Footnotes
    1 Authors GDS and EP contributed equally to this work.
    Elena Putignano
    Footnotes
    1 Authors GDS and EP contributed equally to this work.
    Affiliations
    Institute of Neuroscience (EP, TP), National Research Council, Pisa
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  • Gabriele Chelini
    Affiliations
    Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence
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  • Riccardo Melani
    Affiliations
    Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence
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  • Eleonora Calcagno
    Affiliations
    Department of Neuroscience and National Institute of Neuroscience (EC, MG), University of Turin, Turin
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  • Gian Michele Ratto
    Affiliations
    National Enterprise for Nanoscience and Nanotechnology (GMR), Institute of Nanoscience of the National Research Council, and Scuola Normale Superiore, Pisa
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  • Elena Amendola
    Affiliations
    Mouse Biology Unit (EA, CTG), European Molecular Biology Laboratory, Monterotondo, Italy
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  • Cornelius T. Gross
    Affiliations
    Mouse Biology Unit (EA, CTG), European Molecular Biology Laboratory, Monterotondo, Italy
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  • Author Footnotes
    2 Authors MG and TP contributed equally to this work.
    Maurizio Giustetto
    Footnotes
    2 Authors MG and TP contributed equally to this work.
    Affiliations
    Department of Neuroscience and National Institute of Neuroscience (EC, MG), University of Turin, Turin
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  • Author Footnotes
    2 Authors MG and TP contributed equally to this work.
    Tommaso Pizzorusso
    Correspondence
    Address correspondence to Tommaso Pizzorusso, Ph.D., University of Florence, NEUROFARBA, Area ricerca CNR, Inst Neuroscience via Moruzzi, 1, Pisa 56124, Italy.
    Footnotes
    2 Authors MG and TP contributed equally to this work.
    Affiliations
    Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence

    Institute of Neuroscience (EP, TP), National Research Council, Pisa
    Search for articles by this author
  • Author Footnotes
    1 Authors GDS and EP contributed equally to this work.
    2 Authors MG and TP contributed equally to this work.
Published:September 03, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.08.028

      Abstract

      Background

      CDKL5 (cyclin-dependent kinase-like 5) is mutated in many severe neurodevelopmental disorders, including atypical wRett syndrome. CDKL5 was shown to interact with synaptic proteins, but an in vivo analysis of the role of CDKL5 in dendritic spine dynamics and synaptic molecular organization is still lacking.

      Methods

      In vivo two-photon microscopy of the somatosensory cortex of Cdkl5−/y mice was applied to monitor structural dynamics of dendritic spines. Synaptic function and plasticity were measured using electrophysiological recordings of excitatory postsynaptic currents and long-term potentiation in brain slices and assessing the expression of synaptic postsynaptic density protein 95 (PSD-95). Finally, we studied the impact of insulin-like growth factor 1 (IGF-1) treatment on CDKL5 null mice to restore the synaptic deficits.

      Results

      Adult mutant mice showed a significant reduction in spine density and PSD-95-positive synaptic puncta, a reduction of persistent spines, and impaired long-term potentiation. In juvenile mutants, short-term spine elimination, but not formation, was dramatically increased. Exogenous administration of IGF-1 rescued defective rpS6 phosphorylation, spine density, and PSD-95 expression. Endogenous cortical IGF-1 levels were unaffected by CDKL5 deletion.

      Conclusions

      These data demonstrate that dendritic spine stabilization is strongly regulated by CDKL5. Moreover, our data suggest that IGF-1 treatment could be a promising candidate for clinical trials in CDKL5 patients.

      Keywords

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      Linked Article

      • Insulin-like Growth Factor 1 for Healthy Spines and Healthy Minds?
        Biological PsychiatryVol. 80Issue 4
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          Spines, as dendritic protrusions, harbor most synaptic contacts and, accordingly, serve as critical indicators of neuronal health and function. Pyramidal neurons comprise the major neuronal constituent and output relay of the cerebral cortex and undergo the process of spine remodeling, with the generation of new spines counterbalanced by an equally dynamic process of spine elimination. This ongoing interplay of spine proliferation, growth, and retraction enables cortical neurons to continually adapt their dendritic spine landscape and synaptic connectivity in response to a myriad of internal and external stimuli, thereby providing a basis for the lifelong process of neuronal plasticity and learning.
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