title: Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, [1]) in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to slow the progression of disease.
authors.affiliation: Charles River Discovery Research Services, Kuopio, Finland.
authors.forename: Taneli
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Kimmo
authors.initials: K
authors.lastname: Lehtimäki
authors.forename: Nina
authors.initials: N
authors.lastname: Vartiainen
authors.forename: Jukka
authors.initials: J
authors.lastname: Puoliväli
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hendricks
authors.forename: Jack R
authors.initials: JR
authors.lastname: Glaser
authors.forename: Amyaouch
authors.initials: A
authors.lastname: Bradaia
authors.forename: Kristian
authors.initials: K
authors.lastname: Wadel
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Touller
authors.forename: Outi
authors.initials: O
authors.lastname: Kontkanen
authors.forename: Juha M
authors.initials: JM
authors.lastname: Yrjänheikki
authors.forename: Bruno
authors.initials: B
authors.lastname: Buisson
authors.forename: David
authors.initials: D
authors.lastname: Howland
authors.forename: Vahri
authors.initials: V
authors.lastname: Beaumont
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
authors.forename: Larry C
authors.initials: LC
authors.lastname: Park
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002452:Cell Count; D004195:Disease Models, Animal; D018450:Disease Progression; D023381:Endpoint Determination; D005260:Female; D055879:Gene Knock-In Techniques; D018698:Glutamic Acid / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000473:pathology; D009482:Neurophysiology; D009929:Organ Size; D012091:Repetitive Sequences, Nucleic Acid; D013550:Swimming; D009435:Synaptic Transmission
chemical_list: D009419:Nerve Tissue Proteins; D018698:Glutamic Acid