Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

- RAS-MAPK signaling in different cell types plays distinct role in learning and LTP.
- Enhancing RAS signaling in inhibitory presynaptic neuron impairs learning and LTP.
- Enhancing RAS signaling in excitatory presynaptic neuron enhances learning and LTP.
- Enhancing RAS signaling in excitatory postsynaptic neuron impairs learning and LTP.

The RAS-mitogen-activated protein kinase (MAPK) signaling pathway plays critical roles in brain function, including learning and memory. Mutations of molecules in the RAS-MAPK pathway are associated with a group of disorders called RASopathies, which include Noonan syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome with multiple lentigines, Legius syndrome, and cardio-facio-cutaneous syndrome. RASopathies share certain clinical symptoms, including craniofacial abnormalities, heart defects, delayed growth, and cognitive deficits such as learning disabilities, while each individual syndrome also displays unique phenotypes. Recent studies using mouse models of RASopathies showed that each disorder may have a distinct molecular and cellular etiology depending on the cellular specificity of the mutated molecules. Here, we review the cell-type specific roles of the regulators of the RAS-MAPK pathway in cognitive function (learning and memory) and their contribution to the development of RASopathies. We also discussed recent technical advances in analyzing cell type-specific transcriptomes and proteomes in the nervous system. Understanding specific mechanisms for these similar but distinct disorders would facilitate the development of mechanism-based individualized treatment for RASopathies.