hCyfip1 overexpression in the basolateral amygdala of mice

CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is over-expressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 over-expression, as is observed in patients with CYFIP1 duplication are less well understood. Here, we developed a mouse model of human CYFIP1 overexpression (CYFIP1 OE) to study the effects of excess CYFIP1 on rodent behavior and biological pathways. Extensive behavioral testing of CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes and myelination. We also identified GABA-A subunit composition changes in BLA neurons which are part of the fear conditioning neuronal circuit. Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1. Overall design: Quant seq from the BLA of 16 controls and 15 hCYFIP1 over-expressing mice.