The Noonan Syndrome-linked Raf1L613V mutation drives increased glial number in the mouse cortex and enhanced learning

RASopathies are a family of related syndromes caused by mutations in regulators of the RAS/Extracellular Regulated Kinase 1/2 (ERK1/2) signaling cascade that often result in neurological deficits. RASopathy mutations in upstream regulatory components, such as NF1, PTPN11/SHP2, and RAS have been well-characterized, but mutation-specific differences in the pathogenesis of nervous system abnormalities remain poorly understood, especially those involving mutations downstream of RAS. Here, we assessed cellular and behavioral phenotypes in mice expressing a Raf1(L613V) gain-of-function mutation associated with the RASopathy, Noonan Syndrome. We report that Raf1(L613V/wt) mutants do not exhibit a significantly altered number of excitatory or inhibitory neurons in the cortex. However, we observed a significant increase in the number of specific glial subtypes in the forebrain. The density of GFAP(+) astrocytes was significantly increased in the adult Raf1(L613V/wt) cortex and hippocampus relative to controls. OLIG2(+) oligodendrocyte progenitor cells were also increased in number in mutant cortices, but we detected no significant change in myelination. Behavioral analyses revealed no significant changes in voluntary locomotor activity, anxiety-like behavior, or sociability. Surprisingly, Raf1(L613V/wt) mice mutants performed better than controls in select aspects of the water radial-arm maze, Morris water maze, and cued fear conditioning tasks. Overall, these data show that increased astrocyte and oligodendrocyte progenitor cell (OPC) density in the cortex coincides with enhanced cognition in Raf1(L613V/wt) mutants and further highlight the distinct effects of RASopathy mutations on nervous system development and function. Author summary The RASopathies are a large and complex family of syndromes caused by mutations in the RAS/MAPK signaling cascade with no known cure. Individuals with these syndromes often present with heart defects, craniofacial differences, and neurological abnormalities, such as developmental delay, cognitive changes, epilepsy, and an increased risk of autism. However, there is wide variation in the extent of intellectual ability between individuals. It is currently unclear how different RASopathy mutations affect brain development. Here, we describe the cellular and behavioral consequences of a mutation in a gene called Raf1 that is associated with a common RASopathy, Noonan Syndrome. We find that mice harboring a mutation in Raf1 show moderate increases in the number of two subsets of glial cells, which is also observed in a number of other RASopathy brain samples. Surprisingly, we found that Raf1 mutant mice show improved performance in several learning and memory tasks. Our work highlights potential mutation-specific changes in RASopathy brain function and helps set the framework for future personalized therapeutic approaches.