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

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• 作者：Alessandro Papale^a ; Raffaele d&rsquo ; Isa^b ; ¹ ; Elisabetta Menna^c ; ^e ; ¹ ; Milica Cerovic^a ; ^d ; Nicola Solari^b ; ^d ; Neil Hardingham^a ; Marco Cambiaghi^b ; Marco Cursi^b ; Mariano Barbacid^f ; Letizia Leocani^b ; Stefania Fasano^a ; ^b ; Michela Matteoli^c ; ^e ; Riccardo Brambilla^a ; ^b ; ^{brambillar@cf.ac.uk}
• 关键词：ERK ; GABAergic synaptogenesis ; Intellectual disability ; KRAS ; Pharmacological rescue ; RASopathies
• 刊名：Biological Psychiatry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：81
• 期：3
• 页码：179-192
• 全文大小：8613 K
• 卷排序：81

文摘

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.MethodsWe performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS12V mutant mouse.ResultsThe 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.ConclusionsThese data demonstrate a novel mechanism underlying inhibitory synaptogenesis and provide new insights in understanding mental dysfunctions associated to RASopathies.