Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies

A Papale, R d'Isa, E Menna, M Cerovic, N Solari, N Hardingham, M Cambiaghi, M Cursi, M Barbacid, L Leocani, S Fasano, M Matteoli, R Brambilla

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Abstract

Background: 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. Methods: We performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS12V mutant mouse. Results: The KRAS12V mutation results in a severe form of intellectual disability, which parallels mental deficits found in patients bearing mutations in this gene. KRAS12V mice 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 KRAS12V mice 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. Conclusions: These data demonstrate a novel mechanism underlying inhibitory synaptogenesis and provide new insights in understanding mental dysfunctions associated to RASopathies. © 2016 Society of Biological Psychiatry.
Original languageEnglish
Pages (from-to)179-192
Number of pages14
JournalBiological Psychiatry
Volume81
Issue number3
DOIs
Publication statusPublished - 2017

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Papale, A., d'Isa, R., Menna, E., Cerovic, M., Solari, N., Hardingham, N., Cambiaghi, M., Cursi, M., Barbacid, M., Leocani, L., Fasano, S., Matteoli, M., & Brambilla, R. (2017). Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies. Biological Psychiatry, 81(3), 179-192. https://doi.org/10.1016/j.biopsych.2016.06.016