title: Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies.
abstract: Dysregulation of Ras-extracellular signal-related kinase (ERK) signaling gives rise to RASopathies, a class of neurodevelopmental syndromes associated with intellectual disability. Recently, much attention has been directed at models bearing mild forms of RASopathies whose behavioral impairments can be attenuated by inhibiting the Ras-ERK cascade in the adult. Little is known about the brain mechanisms in severe forms of these disorders.
  
  
  
  We performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS12Vmutant mouse.
  
  
  
  The KRAS12Vmutation results in a severe form of intellectual disability, which parallels mental deficits found in patients bearing mutations in this gene. KRAS12Vmice show a severe impairment of both short- and long-term memory in a number of behavioral tasks. At the cellular level, an upregulation of ERK signaling during early phases of postnatal development, but not in the adult state, results in a selective enhancement of synaptogenesis in gamma-aminobutyric acidergic interneurons. The enhancement of ERK activity in interneurons at this critical postnatal time leads to a permanent increase in the inhibitory tone throughout the brain, manifesting in reduced synaptic transmission and long-term plasticity in the hippocampus. In the adult, the behavioral and electrophysiological phenotypes in KRAS12Vmice can be temporarily reverted by inhibiting gamma-aminobutyric acid signaling but not by a Ras-ERK blockade. Importantly, the synaptogenesis phenotype can be rescued by a treatment at the developmental stage with Ras-ERK inhibitors.
  
  
  
  These data demonstrate a novel mechanism underlying inhibitory synaptogenesis and provide new insights in understanding mental dysfunctions associated to RASopathies.
authors: Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors: Alessandro
authors: A
authors: Papale
authors: Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano.
authors: Raffaele
authors: R
authors: d'Isa
authors: National Research Council (CNR), Neuroscience Institute, Milano; Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Elisabetta
authors: E
authors: Menna
authors: Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom; Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano.
authors: Milica
authors: M
authors: Cerovic
authors: Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano; Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano.
authors: Nicola
authors: N
authors: Solari
authors: Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors: Neil
authors: N
authors: Hardingham
authors: Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano.
authors: Marco
authors: M
authors: Cambiaghi
authors: Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano.
authors: Marco
authors: M
authors: Cursi
authors: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: Mariano
authors: M
authors: Barbacid
authors: Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano.
authors: Letizia
authors: L
authors: Leocani
authors: Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom; Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano.
authors: Stefania
authors: S
authors: Fasano
authors: National Research Council (CNR), Neuroscience Institute, Milano; Humanitas Clinical and Research Center, Rozzano, Italy.
authors: Michela
authors: M
authors: Matteoli
authors: Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom; Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano. Electronic address: brambillar@cf.ac.uk.
authors: Riccardo
authors: R
authors: Brambilla
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials; D008607:Intellectual Disability / Q000378:metabolism*; D017774:Long-Term Potentiation; D020935:MAP Kinase Signaling System; D008569:Memory Disorders / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism; D012919:Social Behavior; D013569:Synapses / Q000502:physiology*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D018079:Receptors, GABA; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ERK; GABAergic synaptogenesis; Intellectual disability; KRAS; Pharmacological rescue; RASopathies