title: 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 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.
authors.affiliation: Department of Neurology, USA; Department of Molecular and Integrative Physiology, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Renoux
authors.affiliation: Department of Neurology, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Sala-Hamrick
authors.affiliation: Department of Neurology, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Carducci
authors.affiliation: Department of Neurology, USA.
authors.forename: M
authors.initials: M
authors.lastname: Frazer
authors.affiliation: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Halsey
authors.affiliation: Department of Molecular and Integrative Physiology, USA; Molecular and Behavioral Neuroscience Institute, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Sutton
authors.affiliation: Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Dolan
authors.affiliation: Department of Molecular and Integrative Physiology, USA; Molecular and Behavioral Neuroscience Institute, USA.
authors.forename: G G
authors.initials: GG
authors.lastname: Murphy
authors.affiliation: Department of Neurology, USA. Electronic address: petertod@umich.edu.
authors.forename: P K
authors.initials: PK
authors.lastname: Todd
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000818:Animals; D001307:Auditory Perception / Q000502:physiology; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000503:physiopathology*; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D065808:Prepulse Inhibition / Q000502:physiology*; D055139:Sensory Gating / Q000502:physiology*; D019680:Trinucleotide Repeat Expansion
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse
keywords: Fragile X; Premutation carrier; Prepulse inhibition; Sensorimotor gating