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

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 tis 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.

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

“…Presently, how the Fmr1 KO mouse processes incoming information is still unclear, because either no differences (Peier et al 2000;Yan et al 2004;Spencer et al 2006;Thomas et al 2012) or enhanced startle responses were shown (Chen and Toth 2001;Nielsen et al 2002;Frankland et al 2004;de Vrij et al 2008;Baker et al 2010;Olmos-Serrano et al 2011;Veeraragavan et al 2012) compared with control animals. However, in one study (Frankland et al 2004), Fmr1 KO mice showed an excessive reaction to auditory stimuli, similar to humans (Renoux et al 2014). Despite the reported discrepancies, it is clear that FMRP plays a role in sensorimotor function/s underlying the altered sensitivity to sensory stimulation observed in both patients and mouse models.…”

Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next

“…In addition, PPI deficits have been identified in other patient populations, including individuals with nocturnal enuresis (Ornitz et al, 1992), Asperger’s syndrome (Howlin and Murphy, 2002; McAlonan et al, 2002), 22q11 syndrome (Sobin et al, 2005), Kleinfelter syndrome (van Rijn et al., 2011), fragile-X syndrome (Frankland et al, 2004; Renoux et al, 2014; Yuhas et al, 2011), and blepharospasm (Gomez-Wong et al, 1998). Some of these studies have used PPI as a quantitative phenotype to understand better the genetics (e.g.…”

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…One approach to capitalize on the validity of PPI models has been to explore the genetic underpinnings of impaired PPI in rodents, to generate or support hypotheses related to the genetic basis of impaired PPI in schizophrenia [and other disorders (e.g., Castellan Baldan et al 2014;Charles et al 2014;Renoux et al 2014)]. Given the numerous brain regions and interconnections known to regulate PPI, it is not surprising that these studies have identified a long list of genes that, by their deletion, suppression, or differential expression, lead to a modification in PPI or its sensitivity to pharmacologic disruption (cf.…”