Deletion of Fmr1 results in sex‐specific changes in behavior

Abstract

ObjectiveIn this study, we used a systemic Fmr1 knockout in order to investigate both genotype‐ and sex‐specific differences across multiple measures of sociability, repetitive behaviors, activity levels, anxiety, and fear‐related learning and memory.BackgroundFragile X syndrome is the most common monogenic cause of intellectual disability and autism. Few studies to date have examined sex differences in a mouse model of Fragile X syndrome, though clinical data support the idea of differences in both overall prevalence and phenotype between the sexes.MethodsUsing wild‐type and systemic homozygous Fmr1 knockout mice, we assessed a variety of behavioral paradigms in adult animals, including the open field test, elevated plus maze, nose‐poke assay, accelerating rotarod, social partition task, three‐chambered social task, and two different fear conditioning paradigms. Tests were ordered such that the most invasive tests were performed last in the sequence, and testing paradigms for similar behaviors were performed in separate cohorts to minimize testing effects.ResultsOur results indicate several sex‐specific changes in Fmr1 knockout mice, including male‐specific increases in activity levels, and female‐specific increases in repetitive behaviors on both the nose‐poke assay and motor coordination on the accelerating rotarod task. The results also indicated that Fmr1 deletion results in deficits in fear learning and memory across both sexes, and no changes in social behavior across two tasks.ConclusionThese findings highlight the importance of including female subjects in preclinical studies, as simply studying the impact of genetic mutations in males does not yield a complete picture of the phenotype. Further research should explore these marked phenotypic differences among the sexes. Moreover, given that treatment strategies are typically equivalent between the sexes, the results highlight a potential need for sex‐specific therapeutics.

Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei ofFmr1Knockout Mice

“…The female Fmr1 KO mice used here contain two alleles of the Fmr1 KO, one on each X-chromosome. Male and female Fmr1 KO mice show differences in behavioral measures ( Nolan et al, 2017 ), vocalization production ( Reynolds et al, 2016 ), and neurophysiology ( Giráldez-Pérez et al, 2013 ; Lokanga et al, 2014 ; Scremin et al, 2015 ), but other studies showed similar behaviors between the sexes ( Ding et al, 2014 ). We found that the auditory brainstem phenotypes we observed did not differ between males and females, suggesting predominantly common molecular mechanisms that are not selectively altered by the mutation.…”

Reversal learning paradigm reveals deficits in cognitive flexibility in the Fmr1 knockout male mouse

“…Fragile X syndrome (FXS) is a neurodevelopmental disorder, caused by a trinucleotide expansion mutation in the FMR1 gene, and is also one of the most prevalent inherited forms of intellectual disability 1 . FXS is often modeled using the Fmr1 knockout (KO) mouse, which can be characterized by several behavioral phenotypes, including alterations in sociability and deficits in fear memory 2 – 4 . Aside from deficits in spatial and non-spatial learning, one understudied facet of intellectual disability is the ability to incorporate new information into existing learning, termed cognitive flexibility.…”

The fragile X mental retardation protein promotes adjustments in cocaine self-administration that preserve reinforcement level

“…Lastly, impairments have been observed for Fmr1 KO and conditional KO mice in flexibility, learning, and memory, including tasks motivated by either reward or aversion (D'Hooge et al, 1997;Mineur et al, 2002;Ding et al, 2014;Nolan et al, 2017), and those explicitly requiring hippocampal function (Zhao et al, 2005;Guo et al, 2011;Arbab et al, 2018). In general, deficits appear to be significantly milder on the C57BL/6 background strain (Spencer et al, 2011).…”