Hickey MA, Kosmalska A, Enayati J, Cohen R, Zeitlin S, Levine MS et al. Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice. Neuroscience 157: 280-295

Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine, Reed Neurological Research Center B114, 710 Westwood Plaza, Los Angeles, CA 90095, USA.
Neuroscience (Impact Factor: 3.36). 09/2008; 157(1):280-95. DOI: 10.1016/j.neuroscience.2008.08.041
Source: PubMed


Huntington's disease is a neurodegenerative disorder, caused by an elongation of CAG repeats in the huntingtin gene. Mice with an insertion of an expanded polyglutamine repeat in the mouse huntingtin gene (knock-in mice) most closely model the disease because the mutation is expressed in the proper genomic and protein context. However, few knock-in mouse lines have been extensively characterized and available data suggest marked differences in the extent and time course of their behavioral and pathological phenotype. We have previously described behavioral anomalies in the open field as early as 1 month of age, followed by the appearance at 2 months of progressive huntingtin neuropathology, in a mouse carrying a portion of human exon 1 with approximately 140 CAG repeats inserted into the mouse huntingtin gene. Here we extend these observations by showing that early behavioral anomalies exist in a wide range of motor (climbing, vertical pole, rotarod, and running wheel performance) and non-motor functions (fear conditioning and anxiety) starting at 1-4 months of age, and are followed by progressive gliosis and decrease in dopamine and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa (DARPP32) (12 months) and a loss of striatal neurons at 2 years. At this age, mice also present striking spontaneous behavioral deficits in their home cage. The data show that this line of knock-in mice reproduces canonical characteristics of Huntington's disease, preceded by deficits which may correspond to the protracted pre-manifest phase of the disease in humans. Accordingly, they provide a useful model to elucidate early mechanisms of pathophysiology and the progression to overt neurodegeneration.

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Available from: Scott Zeitlin, Jan 21, 2014
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    • "It is also used to highlight a depressive-like behavior in rodents, linked to resignation, although the validity of this test as a measure of depression is debatable. Apart from CAG140, all of the HD models that were subjected to this test show a long duration of immobility, which indicates a depressive-like behavior in this paradigm (Grote et al., 2005; Hickey et al., 2008; Peng et al., 2008; Pouladi et al., 2009; Chiu et al., 2011; Renoir et al., 2011; Orvoen et al., 2012; Pouladi et al., 2012; Renoir et al., 2012). A long duration of immobility is associated with either a short swimming duration (YAC 128) (Pouladi et al., 2009), or a short climbing duration (HdhQ111/Q111) (Orvoen et al., 2012). "
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    ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder that is best known for its effect on motor control. Mood disturbances such as depression, anxiety, and irritability also have a high prevalence in patients with HD, and often start before the onset of motor symptoms. Various rodent models of HD recapitulate the anxiety/depressive behavior seen in patients. HD is caused by an expanded polyglutamine stretch in the N-terminal part of a 350 kDa protein called huntingtin (HTT). HTT is ubiquitously expressed and is implicated in several cellular functions including control of transcription, vesicular trafficking, ciliogenesis, and mitosis. This review summarizes progress in efforts to understand the cellular and molecular mechanisms underlying behavioral disorders in patients with HD. Dysfunctional HTT affects cellular pathways that are involved in mood disorders or in the response to antidepressants, including BDNF/TrkB and serotonergic signaling. Moreover, HTT affects adult hippocampal neurogenesis, a physiological phenomenon that is implicated in some of the behavioral effects of antidepressants and is linked to the control of anxiety. These findings are consistent with the emerging role of wild-type HTT as a crucial component of neuronal development and physiology. Thus, the pathogenic polyQ expansion in HTT could lead to mood disorders not only by the gain of a new toxic function but also by the perturbation of its normal function.
    Full-text · Article · Apr 2014 · Frontiers in Behavioral Neuroscience
    • "Knock-in models of HD also exhibit late-onset neurodegeneration. For example, in the CAG140 mouse HD model 38% and 40% reductions in striatal volume and striatal neuron estimates are reported, respectively, in 20-26-month-old animals 9 . While fragment mouse models of HD (e.g. "
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    ABSTRACT: Striatal neuronal degeneration and loss is an important feature of human Huntington's disease (HD). R6/2 HD mice recapitulate many features of human HD including striatal atrophy. While striatal neuronal atrophy and loss is reported in R6/2 HD mice the degree of neuronal loss and the characteristics of cell body atrophy are unclear. We used stereological approaches to estimate whole striatal neuronal numbers and characterize changes in striatal neuronal size distribution. R6/2 HD mice had ~126000 fewer neurons per striatum (~12% decline) at 12 weeks of age than wild-type litter-mates; differences were not present at 5 weeks. Analysis of striatal neuronal numbers per cell body size category revealed declines in neuron numbers in the size ranges 550-1050 µm3 suggesting that larger striatal neurons are more susceptible to atrophy or loss in late stages of disease. R6/2 HD mice have a striatal neuronal loss phenotype. As striatal neuronal loss in human HD is dramatic, neuronal loss in R6/2 striatum provides an important late-stage outcome measure for study of disease modifying interventions.
    No preview · Article · Jan 2014 · PLoS Currents
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    • "Consistent with this was a trend towards decreased anxiety in the light/dark box. Both decreased [59,60] and increased [19,52,61] anxiety have previously been reported in various rodent HD models tested in a number of different paradigms. Our data indicate that decreased anxiety may be a very early response to a single mutant HTT allele, which, as previously hypothesized [59], may reflect the stimulation of repair mechanisms such as the release of anxiolytic neurotrophic factors or a hypercompensatory response. "
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    ABSTRACT: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.
    Full-text · Article · Nov 2013 · PLoS ONE
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