CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes

Abstract

Background 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). 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. Methods We 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. Results Extensive 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. Conclusion 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. Electronic supplementary material The online version of this article (10.1186/s13229-019-0278-0) contains supplementary material, which is available to authorized users.

Cistanches alleviates sevoflurane‐induced cognitive dysfunction by regulating PPAR‐γ‐dependent antioxidant and anti‐inflammatory in rats

“…The open-field test was carried out at day 1 and day 3 post-anaesthesia as described by Fricano et al 21 Briefly, rats were tested in a 27.5 cm × 27.5 cm square arena. The middle, 66% of the arena, was entitled as the 'centre'.…”

Age- and Sex-Specific Fear Conditioning Deficits in Mice Lacking Pcdh10, an Autism Associated Gene

“…Like Pcdh10 +/mice, several mouse models associated with ASD exhibit fear conditioning deficits, including CD38, Homer1a, and Scn1a mutants (Han et al, 2012;Banerjee et al, 2016;Kim et al, 2016), as well as a number of others (Markram et al, 2008;Stapley et al, 2013;Howell et al, 2017;Nolan et al, 2017;Fricano-Kugler et al, 2019). Reports of fear conditioning in individuals with ASD have been varied, with some reporting impairments, and some failing to find differences compared to controls (Bernier et al, 2005;Gaigg and Bowler, 2007;Sterling et al, 2013).…”

Pedagogical Particularities in Correction of Speech Disorders Caused by Genetic Syndromes

“…Расстройства речевой функции этиологически могут быть врожденными [16][17][18], приобретенными [12] и иметь смешанную природу как в случае синдрома Ландау -Клеффнера [19], в этиологии которого отводится роль как воспалительному процессу, так и генетическому компоненту [20].…”

“…Синдром Ангельмана. Этиологическим фатором синдрома Ангельмана является дефект генома участка 15q11.2-q13, 15 хромосомы в виде делеции нескольких миллионов пар азотистых оснований или мутации данного фрагмента ДНК [17].…”

“…В редких случаях возможно наследование от матери. Как правило, случаи появления болезни спорадические [17].…”