title: Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1.
abstract: CDKL5 (cyclin-dependent kinase-like 5) is mutated in many severe neurodevelopmental disorders, including atypical Rett 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence.
authors.forename: Grazia
authors.initials: G
authors.lastname: Della Sala
authors.affiliation: Institute of Neuroscience (EP, TP), National Research Council, Pisa.
authors.forename: Elena
authors.initials: E
authors.lastname: Putignano
authors.affiliation: Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Chelini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Melani
authors.affiliation: Department of Neuroscience and National Institute of Neuroscience (EC, MG), University of Turin, Turin.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Calcagno
authors.affiliation: National Enterprise for Nanoscience and Nanotechnology (GMR), Institute of Nanoscience of the National Research Council, and Scuola Normale Superiore, Pisa.
authors.forename: Gian
authors.initials: G
authors.lastname: Michele Ratto
authors.affiliation: Mouse Biology Unit (EA, CTG), European Molecular Biology Laboratory, Monterotondo, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Amendola
authors.affiliation: Mouse Biology Unit (EA, CTG), European Molecular Biology Laboratory, Monterotondo, Italy.
authors.forename: Cornelius T
authors.initials: CT
authors.lastname: Gross
authors.affiliation: Department of Neuroscience and National Institute of Neuroscience (EC, MG), University of Turin, Turin.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Giustetto
authors.affiliation: Department of Neuroscience, Psychology, Drug Research, and Child Health-Neurofarba, University of Florence, Florence; Institute of Neuroscience (EP, TP), National Research Council, Pisa. Electronic address: tommaso@in.cnr.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pizzorusso
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D000073376:Epileptic Syndromes; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D017966:Pyramidal Cells / Q000473:pathology / Q000648:ultrastructure; D015518:Rett Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D013003:Somatosensory Cortex / Q000473:pathology; D013036:Spasms, Infantile / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D013569:Synapses / Q000187:drug effects / Q000473:pathology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; C533690:CDKL5 protein, mouse; D051528:Guanylate Kinases
keywords: CDKL5; IGF-1; PSD-95; Rett syndrome; dendritic spines; imaging