Transcriptional Alterations and Attentional Deficits in a Rat Model of Fragile X Syndrome

Background: Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. It is a leading monogenic cause of autism spectrum disorder and inherited intellectual disability and is often comorbid with attention deficits. Most FXS cases are due to an expansion of CGG repeats at the 5’ untranslated region of the FMR1 gene leading to suppressed expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA metabolism. We found that a previously published Fmr1 knockout (KO) rat model actually expresses an Fmr1 transcript with an in-frame deletion of exon 8, which encodes a K-homology (KH) RNA-binding domain, KH1. It so happens that several of the few point mutations that are known to cause FXS are found within the KH domains.

Objectives: We aimed to determine whether this previously published Fmr1 KO rat has deficits in attention and in transcriptomic regulation in a region underlying attention, the medial prefrontal cortex (mPFC).

Methods: We used the five-choice serial reaction time task (5-CSRTT) to measure visuospatial attention and RNAseq to evaluate the transcriptional profile of the mPFC.

Results: We observed that an exon 8 deletion in both male and female rats leads to mPFC-associated sustained attention deficits on the 5-CSRTT, similar to what has been observed in FXS patients and Fmr1 KO mice. Furthermore, we found that this deletion leads to alterations in the expression of transcripts within the mPFC, which mapped to two weighted gene co-expression network modules. These modules are conserved in human frontal cortex and enriched for known FMRP targets. Hub genes in these modules represent potential targets for FXS.

Conclusions: The deficit in sustained attention resembles a typical FXS-associated phenotype and suggests that this Fmr1-^∆exon 8 rat models FXS with face validity. Furthermore, these findings provide support for a prefrontal deficit in FXS, indicate that attentional testing might be a reliable cross-species tool for investigating FXS, and identify dysregulated conserved gene networks in a relevant brain region.