Abstract
BackgroundCYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed 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 overexpression, as is observed in patients with CYFIP1 duplication, are less well understood.MethodsWe developed and validated a mouse model of human CYFIP1 overexpression (CYFIP1 OE) using qPCR and western blot analysis. We performed a large battery of behavior testing on these mice, including ultrasonic vocalizations, three-chamber social assay, home-cage behavior, Y-maze, elevated plus maze, open field test, Morris water maze, fear conditioning, prepulse inhibition, and the hot plate assay. We also performed RNA sequencing and analysis on the basolateral amygdala.ResultsExtensive behavioral testing in 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 basolateral amygdala neurons, which are essential components of the neural fear conditioning circuit.ConclusionOverall, 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.
Highlights
Cytoplasmic FMRP-interacting protein 1 (CYFIP1), a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in 15q duplication syndrome (Dup15q) syndrome as well as autism spectrum disorder (ASD)
Creation and characterization of CYFIP-overexpressing mice To characterize the consequences of CYFIP1 overexpression on mouse behavior, we utilized the Mouse Biology Program at UC Davis to create CYFIP1overexpressing transgenic (Tg) mouse lines using pronuclear injection of a human-CYFIP1 bacterial artificial chromosome (BAC) (Fig. 1a)
BAC in line 1 and line 2 were 5.4 and 6.0, respectively (Fig. 1b). mRNA transcripts for hCYFIP1 at p60 were significantly increased in the cortex and hippocampus in both lines compared to their wild-type (WT) littermates (Fig. 1c, Additional file 3: Table S1)
Summary
CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed in Dup15q syndrome as well as autism spectrum disorder (ASD). Analysis of genes in the BP1-2 region is of increasing interest. We focus on the effect of overexpressing one of the four genes harbored in the BP1-2 region, CYFIP1 (cytoplasmic FMRP-interacting protein 1). CYFIP1 deletion in 15q11.2 syndrome increases risk for developmental disorders including schizophrenia [13]. (4) Post-mortem analysis of patients with Dup15q has revealed significant overexpression of CYFIP1 in the brain, ranging from three to 24-fold depending on the specific form of Dup15q [16, 17]. While CYFIP1 is overexpressed in ASD brain and present in the region of duplication associated with ASD, the specific contributions of CYFIP1 overexpression on ASD-associated behaviors remain unknown
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