Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice.

Rachel Saré,Christopher Figueroa,Carolyn Beebe Smith,Abigail Lemons,Inna Loutaev

doi:10.3390/brainsci9010013

Rachel Saré, Christopher Figueroa + Show 3 more

Open Access

https://doi.org/10.3390/brainsci9010013

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Abstract

Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, FXR1P, and FXR2P. The functions of FXR1P and FXR2P and their possible roles in producing or modulating the phenotype observed in FXS are yet to be identified. Previous studies have revealed that mice lacking Fxr2 display similar behavioral abnormalities as Fmr1 knockout (KO) mice. In this study, we expand upon the behavioral phenotypes of Fmr1 KO and Fxr2+/− (Het) mice and compare them with Fmr1 KO/Fxr2 Het mice. We find that Fmr1 KO and Fmr1 KO/Fxr2 Het mice are similarly hyperactive compared to WT and Fxr2 Het mice. Fmr1 KO/Fxr2 Het mice have more severe learning and memory impairments than Fmr1 KO mice. Fmr1 KO mice display significantly impaired social behaviors compared to WT mice, which are paradoxically reversed in Fmr1 KO/Fxr2 Het mice. These results highlight the important functional consequences of loss or reduction of FMRP and FXR2P.

Highlights

Fragile X syndrome (FXS) is the leading heritable cause of intellectual disability in humans, affecting about 1 in 4000 males [1]
We hypothesized that Fmr1 KO/Fxr2 Het mice would have an exaggerated behavioral phenotype compared to either single mutation. We found that both Fmr1 KO and Fmr1 KO/Fxr2 Het mice are hyperactive compared to wild-type (WT) and Fxr2 Het mice
FXR2 protein expression was reduced by 60% in Fxr2 heterozygous animals compared to controls (p = 0.0001, expression was reduced by 60% in Fxr2 heterozygous animals compared to controls (p = 0.0001, student’s t-test) (Figure 1)

Summary

Introduction

Fragile X syndrome (FXS) is the leading heritable cause of intellectual disability in humans, affecting about 1 in 4000 males [1]. FXS is primarily caused by a CGG repeat expansion in the 50 UTR of FMR1 which leads to gene silencing and the consequent loss of its protein product, FMRP [3]. FMRP is highly expressed in the brain, and is thought to act as a translational suppressor [5]. The loss of translational regulation by FMRP has been shown to lead to excessive brain protein synthesis in Fmr knockout (KO) mice, a mouse model of FXS [6]. In addition to its presumed role in mRNA regulation, FMRP is thought to be involved in nuclear export and cytoplasmic transport [7], ion channel activity [8], and participates in the DNA damage response [9]

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