Elsevier

Behavioural Brain Research

Volume 267, 1 July 2014, Pages 42-45
Behavioural Brain Research

Short Communication
Impaired sensorimotor gating in Fmr1 knock out and Fragile X premutation model mice

https://doi.org/10.1016/j.bbr.2014.03.013Get rights and content

Highlights

  • FMR1 KO Fragile X syndrome model mice show impaired prepulse inhibition (PPI).

  • CGG repeat knockin FXTAS model mice show impaired prepulse inhibition.

  • These prepulse inhibition abnormalities in CGG knockin mice are age-dependent.

  • Fmr1 KO and CGG knockin animals share an impaired PPI phenotype.

Abstract

Fragile X syndrome (FXS) is a common inherited cause of intellectual disability that results from a CGG repeat expansion in the FMR1 gene. Large repeat expansions trigger both transcriptional and translational suppression of Fragile X protein (FMRP) production. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an allelic neurodegenerative disease caused by smaller “pre-mutation” CGG repeat expansions that enhance FMR1 transcription but lead to translational inefficiency and reduced FMRP expression in animal models. Sensorimotor gating as measured by pre-pulse inhibition (PPI) is altered in both FXS patients and Fmr1 knock out (KO) mice. Similarly, FXTAS patients have demonstrated PPI deficits. Recent work suggests there may be overlapping synaptic defects between Fmr1 KO and CGG knock-in premutation mouse models (CGG KI). We therefore sought to interrogate PPI in CGG KI mice. Using a quiet PPI protocol more akin to human testing conditions, we find that Fmr1 KO animals have significantly impaired PPI. Using this same protocol, we find CGG KI mice demonstrate an age-dependent impairment in PPI compared to wild type (WT) controls. This study describes a novel phenotype in CGG KI mice that can be used in future therapeutic development targeting premutation associated symptoms.

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      FMRP, the protein product of Fmr1 gene, is expressed across all levels of the central auditory system, including strong expression in the cochlear nucleus and other regions of the brainstem (Zorio et al., 2017). Abnormal functions of these regions in Fmr1 KO mice have been reported (Garcia-Pino et al., 2017; Mott and Wei, 2014; Wang et al., 2018) and both humans with FXS and Fmr1 KO mice show altered ASR and PPI responses (human: Frankland et al., 2004; Yuhas et al., 2011; Hessl et al., 2009; mouse: Chen and Toth, 2001; Nielsen et al., 2002; Renoux et al., 2014; Yun et al., 2006). One of FMRP’s translational targets is matrix metalloproteinase-9 (MMP-9), an endopeptidase important in CNS development through extracellular matrix remodeling and synaptic plasticity (Reinhard et al., 2015).

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      PPI is deficient in SCZ patients and in some other neuropsychiatric disorders and can be measured across different species (Powell et al., 2012; Swerdlow et al., 2008). In an effort to mimic the PPI testing conditions used in patient studies, we recorded PPI using an established protocol with minimal background noise (Renoux et al., 2014). The startle response to a brief loud sound (20 ms, 120 dB) or the response to “analog” (quiet trial, no auditory stimulation) was analyzed.

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    These authors contributed equally to this work.

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