Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1

Carla E M Golden,Jason P Lerch,Yohan Yee,Patrick R Hof,Victoria X Wang,Joseph D Buxbaum,Hala Harony-Nicolas

doi:10.1038/s41398-020-00943-x

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by mutations in the FMR1 gene. Neuroanatomical alterations have been reported in both male and female individuals with FXS, yet the morphological underpinnings of these alterations have not been elucidated. In the current study, we found structural changes in both male and female rats that model FXS, some of which are similarly impaired in both sexes, including the superior colliculus and periaqueductal gray, and others that show sex-specific changes. The splenium of the corpus callosum, for example, was only impaired in males. We also found reduced axonal caliber in the splenium, offering a mechanism for its structural changes. Furthermore, we found that overall, male rats have higher brain-wide diffusion than female rats. Our results provide insight into which brain regions are vulnerable to a loss of Fmr1 expression and reveal an impairment at the level of the axon that could cause structural changes in white matter regions.

Highlights

Introduction FragileX syndrome (FXS) is a monogenic disorder caused by mutations in the FMR1 gene, which encodes fragile X mental retardation protein (FMRP)
We recently identified a sustained attention deficit that presented in both sexes of a rat model of Fragile X syndrome (FXS) that has a deletion of an mRNA-binding domain called the Khomology 1 (KH1) domain[11]
There was a significant effect of sex on absolute and relative volume of the superior colliculus and relative volume of the fourth ventricle (Fig. 2a, b; linear model (LM) followed by Tukey HSD, p adj. = 4.4 × 10−13 and p adj. = 5.08 × 10−8 and two-way ANOVA followed by Tukey HSD, p adj. = 1.43 × 10−4 respectively)

Summary

Introduction

X syndrome (FXS) is a monogenic disorder caused by mutations in the FMR1 gene, which encodes fragile X mental retardation protein (FMRP). It is the leading monogenic cause of autism spectrum disorder (ASD), the most frequent known form of inherited intellectual disability (ID), is often comorbid with attention-deficit/hyperactivity disorder (ADHD), and can cause sensory hyperarousal[1,2]. Structural deficits in white matter have been identified in Fmr[1] knockout (KO) mice and resemble those seen in individuals with FXS5–7 This includes regions known to be recruited during visuospatial attention, namely, the superior colliculus, the splenium of the corpus callosum, and the white matter of the medial prefrontal cortex. We predict that similar regions will be impaired in a rat model of FXS

Methods

Results

Conclusion