Mapping pathological phenotypes in a mouse model of CDKL5 disorder.
Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Elena
E
Amendola
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Yang
Y
Zhan
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Camilla
C
Mattucci
Department of Neuroscience and National Institute of Neuroscience, University of Turin, Turin, Italy.
Enrico
E
Castroflorio
Department of Neuroscience and National Institute of Neuroscience, University of Turin, Turin, Italy.
Eleonora
E
Calcagno
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Claudia
C
Fuchs
Institute of Neuroscience, National Research Council (CNR), Pisa, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA University of Florence, Florence, Italy.
Giuseppina
G
Lonetti
Institute of Neuroscience, National Research Council (CNR), Pisa, Italy.
Davide
D
Silingardi
Institute of Neuroinformatics, University of Zürich and Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.
Alexei L
AL
Vyssotski
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Dominika
D
Farley
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Elisabetta
E
Ciani
Institute of Neuroscience, National Research Council (CNR), Pisa, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA University of Florence, Florence, Italy.
Tommaso
T
Pizzorusso
Department of Neuroscience and National Institute of Neuroscience, University of Turin, Turin, Italy.
Maurizio
M
Giustetto
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
Cornelius T
CT
Gross
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003712:Dendrites / Q000473:pathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D000073376:Epileptic Syndromes; D005074:Evoked Potentials, Visual / Q000502:physiology; D005133:Eye Movements / Q000502:physiology; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016548:Prosencephalon / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology*; D018709:Statistics, Nonparametric
D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human