Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy

• Published in: PLoS genetics 2017-03, Vol.13 (3), p.e1006684-e1006684
• Main Authors: Altmüller, Franziska, Pothula, Santosh, Annamneedi, Anil, Nakhaei-Rad, Saeideh, Montenegro-Venegas, Carolina, Pina-Fernández, Eneko, Marini, Claudia, Santos, Monica, Schanze, Denny, Montag, Dirk, Ahmadian, Mohammad R, Stork, Oliver, Zenker, Martin, Fejtova, Anna
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Animals; Behavior; Biochemistry; Biology and Life Sciences; Blotting, Western; Brain; Cells, Cultured; Cognitive ability; Computer and Information Sciences; Congenital heart defects; Disease Models, Animal; DNA microarrays; Exploratory behavior; Forebrain; Gene Expression; Gene Expression Profiling - methods; Gene mutation; Gene regulation; Genetic aspects; Genetic regulation; Genetics; Glutamate receptors; Glutamic acid receptors; Hippocampal plasticity; Hippocampus; Humans; Kinases; MAP kinase; Maze Learning - physiology; Memory; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; Molecular modelling; Mutation; Neural plasticity; Neurobiology; Neurochemistry; Neurons; Neurons - metabolism; Neuroplasticity; Neurosciences; Noonan syndrome; Noonan Syndrome - genetics; Noonan Syndrome - metabolism; Noonan Syndrome - physiopathology; Noonan's syndrome; Phosphatase; Prosencephalon - metabolism; Prosencephalon - pathology; Protein transport; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Proteins; Ras protein; ras Proteins - genetics; ras Proteins - metabolism; Research and Analysis Methods; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Signal transduction; Signal Transduction - genetics; Stem cells; Studies; Synaptic plasticity; TOR protein
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006684

Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regulated Ras signaling in brains and neuronal cultures derived from this model. We observed an altered surface expression and trafficking of synaptic glutamate receptors, which are crucial for hippocampal neuronal plasticity. Furthermore, we show that the neuronal activity-induced ERK signaling, as well as the consecutive regulation of gene expression are strongly perturbed. Microarray-based hippocampal gene expression profiling revealed profound differences in the basal state and upon stimulation of neuronal activity. The neuronal activity-dependent gene regulation was strongly attenuated in Ptpn11D61Y neurons. In silico analysis of functional networks revealed changes in the cellular signaling beyond the dysregulation of Ras/MAPK signaling that is nearly exclusively discussed in the context of NS at present. Importantly, changes in PI3K/AKT/mTOR and JAK/STAT signaling were experimentally confirmed. In summary, this study uncovers aberrant neuronal activity-induced signaling and regulation of gene expression in Ptpn11D61Y mice and suggests that these deficits contribute to the pathophysiology of cognitive impairments in NS.