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Impaired sensorimotor gating in Fmr1 knock out and Fragile X premutation model mice
A J Renoux1, K J Sala-Hamrick2, N M Carducci2
1Department of Neurology, USA; Department of Molecular and Integrative Physiology, USA.
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.
Insights
Fragile X syndrome (FXS) and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) involve FMR1 gene CGG repeat expansions. This study reveals an age-dependent sensorimotor gating deficit in CGG knock-in mice, offering a new model for FXTAS research.
Area of Science:
- Neurogenetics
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Fragile X syndrome (FXS) stems from CGG repeat expansion in the FMR1 gene, causing intellectual disability.
- Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is linked to FMR1 premutations, leading to neurodegeneration.
- Sensorimotor gating deficits, measured by pre-pulse inhibition (PPI), are observed in both FXS and FXTAS.
Purpose of the Study:
- To investigate sensorimotor gating (PPI) in FMR1 CGG knock-in (KI) mice, a model for FXTAS.
- To compare PPI deficits in FMR1 knock-out (KO) and CGG KI mice.
- To establish a novel phenotype in CGG KI mice for therapeutic development.
Main Methods:
- Utilized a quiet pre-pulse inhibition (PPI) protocol, mimicking human testing conditions.
- Assessed PPI in FMR1 knock-out (KO) mice.
- Evaluated PPI in CGG knock-in (KI) mice across different ages and compared them to wild-type (WT) controls.
Main Results:
- FMR1 KO mice exhibited significantly impaired PPI.
- CGG KI mice demonstrated an age-dependent impairment in PPI compared to WT controls.
- This study identified a novel phenotype in CGG KI mice relevant to FXTAS.
Conclusions:
- FMR1 KO mice show significant sensorimotor gating deficits.
- CGG KI mice display an age-dependent PPI impairment, mirroring FXTAS symptoms.
- The CGG KI mouse model offers a valuable tool for studying and developing therapies for FXTAS.
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