Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease

PLoS One. 2012;7(12):e50717. doi: 10.1371/journal.pone.0050717. Epub 2012 Dec 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal*
  • Body Weight
  • Brain / metabolism
  • Brain / pathology*
  • Brain / physiopathology
  • Cell Count
  • Disease Models, Animal*
  • Disease Progression
  • Endpoint Determination
  • Female
  • Gene Knock-In Techniques*
  • Glutamic Acid / metabolism
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / pathology*
  • Huntington Disease / physiopathology*
  • Magnetic Resonance Imaging
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Neostriatum / pathology
  • Nerve Tissue Proteins / genetics
  • Neurons / pathology
  • Neurophysiology*
  • Organ Size
  • Repetitive Sequences, Nucleic Acid
  • Swimming
  • Synaptic Transmission

Substances

  • Nerve Tissue Proteins
  • Glutamic Acid

Grant support

CHDI Foundation is a not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington's disease. The research described was conducted by Charles River under a fee-for-service agreement for CHDI Foundation in collaboration with and funded by CHDI Foundation. The funder, through CHDI Management, fully participated in study design, data collection and analysis, the decision to publish, and preparation of the manuscript. CHDI Foundation has recently provided financial support to the Public Library of Science for PLoS Currents: Huntington Disease.