CARDIO-FACIO-CUTANEOUS SYNDROME (CFCS) ASSOCIATED BRAF<SUP>Q241R</SUP> MUTATION INFLUENCES SPATIAL WORKING MEMORY AND TASK-RELATED NEURONAL ACTIVITY IN FRONTO-TEMPORAL CIRCUITS

Cardio-facio-cutaneous syndrome (CFCS) is a rare neurodevelopmental RASopathy characterized by severe intellectual disability, seizures and autistic features. These symptoms are often underdiagnosed and currently lack approved therapeutic options. CFCS is most commonly caused by mutations in the BRAF gene. In this study, we investigated disease-related phenotypes in a newly-generated CFCS mouse model featuring forebrain-specific expression of the BRAF^Q241R mutation (which corresponds to the most prevalent CFC-linked BRAF^Q257R variant in humans). Specifically, we evaluated the impact of this mutation on cellular signaling, neuronal activation patterns and cognitive function. First, we evaluated the BRAF activity, regulation of the RAS-MAPK signaling cascade and downstream gene expression in the cerebral cortex of BRAF^Q241R mutant mice across postnatal development, in order to assess the development stage-dependent modulation of this pathway in the context of BRAF^Q241R mutation. In order to visualize neuronal activation patterns in circuits associated with learning and memory processes, we quantified c-Fos immunoreactivity in brain sections. We show that task-dependent increases in c-Fos expression are occluded in the medial prefrontal cortex (mPFC), CA1 and anterior cingulate cortex (ACC) of BRAF^Q241R mutants. Conversely, novelty increased the neuronal c-Fos expression in BRAF^Q241R mutants similar to controls, indicating that novelty- or arousal-dependent neural activation remains intact in these mice. Overall, these findings support our hypothesis that CFCS-associated BRAF^Q241R mutation affects fronto-temporal circuitry and might impair learning and memory.