Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models

被引：247

作者：

Menalled, Liliana ^{[1
]}

El-Khodor, Bassem F. ^{[1
]}

Patry, Monica ^{[1
]}

Suarez-Farinas, Mayte ^{[2
]}

orenstein, Samantha J. ^{[1
]}

Zahasky, Benjamin ^{[1
]}

Leahy, Christina ^{[1
]}

Wheeler, Vanessa ^{[3
]}

Yang, X. William ^{[4
,5
,6
]}

MacDonald, Marcy ^{[3
]}

Morton, A. Jennifer ^{[7
]}

Bates, Gill ^{[8
]}

Leeds, Janet ^{[9
]}

Park, Larry ^{[9
]}

Howland, David ^{[9
]}

Signer, Ethan ^{[9
]}

Tobin, Allan ^{[9
]}

Brunner, Daniela ^{[1
,10
]}

机构：

[1] PsychoGenics Inc, Tarrytown, NY 10591 USA

[2] Rockefeller Univ Hosp, New York, NY 10065 USA

[3] Massachusetts Gen Hosp, Mol Neurogenet Lab, Charlestown, MA 02129 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA

[7] Univ Cambridge, Dept Pharmacol, Cambridge CB2 1PD, England

[8] Kings Coll London, Sch Med, Dept Med & Mol Genet, London SE1 9RT, England

[9] CHDI Fdn, New York, NY 10001 USA

[10] Columbia Univ, Dept Psychiat, New York, NY 10032 USA

来源：

NEUROBIOLOGY OF DISEASE | 2009年 / 35卷 / 03期

关键词：

ENVIRONMENTAL ENRICHMENT; MUTANT HUNTINGTIN; CAG REPEAT; TRINUCLEOTIDE REPEAT; PREPULSE INHIBITION; STARTLE RESPONSE; MOTOR DEFICITS; MICE; ABNORMALITIES; HD;

D O I：

10.1016/j.nbd.2009.05.007

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Huntington's disease (HD) is one of the few neurodegenerative diseases with a known genetic cause, knowledge that has enabled the creation of animal models using genetic manipulations that aim to recapitulate HD pathology. The study of behavioral and neuropathological phenotypes of these HD models, however, has been plagued by inconsistent results across laboratories stemming from the lack of standardized husbandry and testing conditions, in addition to the intrinsic differences between the models. We have compared different HD models using standardized conditions to identify the most robust phenotypic differences, best suited for preclinical therapeutic efficacy studies. With a battery of tests of sensory-motor function, such as the open field and prepulse inhibition tests, we replicate previous results showing a strong and progressive behavioral deficit in the R6/2 line with an average of 129 CAG repeats in a mixed CBA/J and C57BL/6J background. We present the first behavioral characterization of a new model, an R6/2 line with an average of 248 CAG repeats in a pure C57BL/6J background, which also showed a progressive and robust phenotype. The BACHD in a FVB/N background showed robust and progressive behavioral phenotype, while the YAC128 full-length model on either an FVB/N or a C57BL/6J background generally showed milder deficits. Finally, the Hdh(Q111) knock-in mouse on a CD1 background showed very mild deficits. This first extensive standardized cross-characterization of several HD animal models under standardized conditions highlights several behavioral outcomes, such as hypoactivity, amenable to standardized preclinical therapeutic drug screening. (C) 2009 Elsevier Inc. All rights reserved.

引用

页码：319 / 336

页数：18

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