Genetic mouse models of Huntington's and Parkinson's diseases: Illuminating but imperfect

Mental Retardation Research Center, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Trends in Neurosciences (Impact Factor: 13.56). 12/2004; 27(11):691-7. DOI: 10.1016/j.tins.2004.08.008
Source: PubMed


Genetic mouse models based on identification of genes that cause Huntington's and Parkinson's diseases have revolutionized understanding of the mechanistic pathophysiological progression of these disorders. These models allow the earliest manifestations of the diseases to be identified, and they display behavioral, neuropathological and electrophysiological deficits that can be followed over time in mechanistic and drug studies. An intriguing feature is that they do not reproduce the relatively selective and massive cell loss characterizing the human diseases. There is more information on Huntington's disease models because the disorder involves a single gene that was identified over ten years ago; genetic mutations causing Parkinson's disease are rare and were discovered more recently, and models of the disease have been generated only within the past few years.

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    • "Alterations in striatal PKA function have been shown to impair motor execution and motor learning (Brandon et al., 1998; Chagniel et al., 2014; Kheirbek et al., 2009). In HD, severe neuronal dysfunction precedes degeneration and is probably the major cause of many motor symptoms (Levine et al., 2004). Therefore, we hypothesized that normalization of PKA activity in the striatum could also benefit motor abnormalities . "
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    ABSTRACT: Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease. Copyright © 2014. Published by Elsevier Inc.
    Neurobiology of Disease 11/2014; 74C:41-57. DOI:10.1016/j.nbd.2014.11.004 · 5.08 Impact Factor
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    • "To study the underlying mechanisms of sleep-wake disturbances associated with HD, we first need to identify suitable animal models that recapitulate as many symptom sets of HD as possible. While there are numerous mouse models of HD, no single model has yet been determined to be the ideal mirror of human HD [17]. Two examples of transgenic insertion HD mouse models are the exon 1-fragment model (R6/2 [18]) and the stable 90Q-repeat with full-length human HTT gene model (BACHD [19]). "
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    ABSTRACT: Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington's disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur.
    PLoS ONE 07/2013; 8(7):e69993. DOI:10.1371/journal.pone.0069993 · 3.23 Impact Factor
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    • "Other structures such as the globus pallidus, thalamus, hypothalamus, subthalamic nucleus (STN), and substantia nigra also are affected, particularly in the later stages (Kremer et al., 1990; Heinsen et al., 1996; Petersen et al., 2005). Although the symptomatology of HD is classically attributed to striatal and cortical neuronal loss, studies have demonstrated that neuronal dysfunction precedes cell death (Tobin and Signer, 2000; Levine et al., 2004). For example , psychiatric, cognitive, and motor symptoms can and often appear alongside cellular and synaptic alterations in the absence of neuronal loss (Vonsattel and Difiglia, 1998). "
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    ABSTRACT: Dopamine (DA) plays an essential role in the control of coordinated movements. Alterations in DA balance in the striatum lead to pathological conditions such as Parkinson's and Huntington's diseases (HD). HD is a progressive, invariably fatal neurodegenerative disease caused by a genetic mutation producing an expansion of glutamine repeats and is characterized by abnormal dance-like movements (chorea). The principal pathology is the loss of striatal and cortical projection neurons. Changes in brain DA content and receptor number contribute to abnormal movements and cognitive deficits in HD. In particular, during the early hyperkinetic stage of HD, DA levels are increased whereas expression of DA receptors is reduced. In contrast, in the late akinetic stage, DA levels are significantly decreased and resemble those of a Parkinsonian state. Time-dependent changes in DA transmission parallel biphasic changes in glutamate synaptic transmission and may enhance alterations in glutamate receptor-mediated synaptic activity. In this review, we focus on neuronal electrophysiological mechanisms that may lead to some of the motor and cognitive symptoms of HD and how they relate to dysfunction in DA neurotransmission. Based on clinical and experimental findings, we propose that some of the behavioral alterations in HD, including reduced behavioral flexibility, may be caused by altered DA modulatory function. Thus, restoring DA balance alone or in conjunction with glutamate receptor antagonists could be a viable therapeutic approach.
    Frontiers in Neuroscience 07/2013; 7(7):114. DOI:10.3389/fnins.2013.00114 · 3.66 Impact Factor
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