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
