Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington's disease

Aldrin E. Molero, Eduardo E. Arteaga-Bracho, Christopher H. Chen, Maria E. Gulinello, Michael L. Winchester, Nandini Pichamoorthy, Solen Gokhan, Kamran Khodakhah, Mark F. Mehler

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37 Citations (Scopus)

Abstract

Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington's disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-CreERT2 mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHttexon1 was removed and mHtt expression was terminated (Q97CRE). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.

Original languageEnglish (US)
Pages (from-to)5736-5741
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number20
DOIs
StatePublished - May 17 2016

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Huntington Disease
Corpus Striatum
Disease Progression
Neurogenesis
N-Methylaspartate
Tamoxifen
Embryonic Stem Cells
Exons
Cell Line

Keywords

  • Neurodegeneration
  • Plasticity
  • Prodromal

ASJC Scopus subject areas

  • General

Cite this

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington's disease. / Molero, Aldrin E.; Arteaga-Bracho, Eduardo E.; Chen, Christopher H.; Gulinello, Maria E.; Winchester, Michael L.; Pichamoorthy, Nandini; Gokhan, Solen; Khodakhah, Kamran; Mehler, Mark F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 20, 17.05.2016, p. 5736-5741.

Research output: Contribution to journalArticle

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