Q241R mutation of Braf gene causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome independent of developmental malformations

Constitutively active mutants of Braf cause cardio-facio-cutaneous (CFC) syndrome, which is characterized by growth and developmental defects, cardiac malformations, characteristic facial features, cutaneous manifestations, and mental retardation. An animal model of human CFC syndrome, a systemic BrafQ241R/+ mutant mouse has been reported to exhibit multiple CFC syndrome-like phenotypes. In this study, we analyzed the effects of Braf mutation on neural functions separately from their effects on developmental processes. To this end, we generated Braf mutant mice that express BrafQ241R specifically in mature excitatory neurons (n-BrafQ241R/+). We found no growth retardation or cardiac malformations in n-BrafQ241R/+ mice, indicating normal development of these mice. Behavioral analysis revealed that the mutant mice exhibited decreased locomotor activity and exploratory behavior, enhanced auditory startle response, and impaired hippocampus-dependent learning, many of which were similar to the systemic BrafQ241R/+ mouse. In the hippocampus of n-BrafQ241R/+ mice, the long-term potentiation of synaptic transmission was enhanced, and active forms of ERK1/2 were increased. Transcriptome analysis of hippocampal tissue revealed significant changes in the expression of genes involved in synaptic function and memory learning, as well as increased expression of Dusp6 and Spred3, suppressors of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. These data suggest that the neuronal dysfunction observed in the systemic CFC mouse model is due to the disruption of homeostasis of RAS/MAPK signaling pathway by the activated Braf mutant after maturation, rather than abnormal development of the brain, and a similar mechanism may be possible in human CFC syndrome.