ALTERATIONS IN K-RAS SIGNALING AND SYNAPTIC FUNCTION ASSOCIATED TO THE NOONAN SYNDROME (K-RASV14I)

K-Ras belongs to the Ras family of small GTPases, which act as molecular switches regulating signaling pathways involved in cell growth and differentiation, mainly through the MAPK/ERK and PI3K/Akt/mTOR cascades. Ras signaling is an important mediator of synaptic plasticity in the brain. In the hippocampus, particularly at the Schaffer collateral–CA1 synapse, our group has shown that neuronal K-Ras is essential for NMDAR-dependent long-term potentiation (LTP).
Mutations in Ras/MAPK pathway genes cause RASopathies, a group of neurodevelopmental disorders that includes Noonan syndrome. K-Ras mutations are associated with some forms of this syndrome that present more severe phenotypes. Among the 18 known germline variants, K-RasV14I is one of the most frequent. This variant confers a moderate gain-of-function, with intermediate GTPase activity and increased nucleotide exchange, leading to greater accumulation of active, GTP-bound K-Ras. However, its effects in the brain have not been studied yet.
Here, we have investigated the impact of the K-RasV14I on neuronal and astrocytic signaling and synaptic plasticity, using organotypic hippocampal slice cultures with cell type-specific lentiviral expression of K-RasWT or K-RasV14I and heterozygous knockin K-RasV14I mice.
Our initial findings suggest that the K-Ras mutation associated with Noonan syndrome alters neuronal morphology and astrocyte-neuron communication during synaptic plasticity at hippocampal CA3-CA1 synapses. Ongoing experiments will further address mechanistic aspects of this modulation.