Genetic Mouse Models of Huntington's Disease: Focus on Electrophysiological Mechanisms

Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA.
ASN Neuro (Impact Factor: 4.02). 05/2010; 2(2):e00033. DOI: 10.1042/AN20090058
Source: PubMed


The discovery of the HD (Huntington's disease) gene in 1993 led to the creation of genetic mouse models of the disease and opened the doors for mechanistic studies. In particular, the early changes and progression of the disease could be followed and examined systematically. The present review focuses on the contribution of these genetic mouse models to the understanding of functional changes in neurons as the HD phenotype progresses, and concentrates on two brain areas: the striatum, the site of most conspicuous pathology in HD, and the cortex, a site that is becoming increasingly important in understanding the widespread behavioural abnormalities. Mounting evidence points to synaptic abnormalities in communication between the cortex and striatum and cell-cell interactions as major determinants of HD symptoms, even in the absence of severe neuronal degeneration and death.

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    • "The most commonly used, well-characterized HD models do not accurately reproduce human HD genetics. Specifically, they express either mouse HTT with expanded polyQ repeats (knock-in models) or human muHTT on a mouse wild-type HTT background (fragment and full-length transgenic models; reviewed in: [9], [10]). To overcome these obstacles, a new “humanized” mouse model termed Hu97/18 has been developed, and behavioral and neuropathological tests have shown it recapitulates many aspects of HD [11]. "
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    ABSTRACT: Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the gene (HTT) encoding the huntingtin protein (HTT). This mutation leads to multiple cellular and synaptic alterations that are mimicked in many current HD animal models. However, the most commonly used, well-characterized HD models do not accurately reproduce the genetics of human disease. Recently, a new 'humanized' mouse model, termed Hu97/18, has been developed that genetically recapitulates human HD, including two human HTT alleles, no mouse Hdh alleles and heterozygosity of the HD mutation. Previously, behavioral and neuropathological testing in Hu97/18 mice revealed many features of HD, yet no electrophysiological measures were employed to investigate possible synaptic alterations. Here, we describe electrophysiological changes in the striatum and hippocampus of the Hu97/18 mice. At 9 months of age, a stage when cognitive deficits are fully developed and motor dysfunction is also evident, Hu97/18 striatal spiny projection neurons (SPNs) exhibited small changes in membrane properties and lower amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs); however, release probability from presynaptic terminals was unaltered. Strikingly, these mice also exhibited a profound deficiency in long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, at 6 months of age we found only subtle alterations in SPN synaptic transmission, while 3-month old animals did not display any electrophysiologically detectable changes in the striatum and CA1 LTP was intact. Together, these data reveal robust, progressive deficits in synaptic function and plasticity in Hu97/18 mice, consistent with previously reported behavioral abnormalities, and suggest an optimal age (9 months) for future electrophysiological assessment in preclinical studies of HD.
    PLoS ONE 04/2014; 9(4):e94562. DOI:10.1371/journal.pone.0094562 · 3.23 Impact Factor
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    • "There are several genetic rodent models established to investigate the pathogenesis of the devastating diseases [e.g. (Elder et al. 2010) for AD; (Cepeda et al. 2010) for HD, and (Magen and Chesselet 2010) for PD]. Although in most cases these models do not completely reflect the phenotypes observed in patients, they serve very valuable subjects to decipher some basic aspects of the cellular changes occurring during AD, HD or PD. "
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    Biogerontology 10/2013; 14(6). DOI:10.1007/s10522-013-9469-9 · 3.29 Impact Factor
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    • "Alterations in quantitative electroencephalographic measures in R6 / 2 mice Altered electrophysiology and corticostriatal processing is a salient feature of preclinical Huntington ' s disease models ( Rebec et al . , 2006 ; Miller et al . , 2008 , 2011 ; Walker et al . , 2008 ) and is evi - dent at the level of individual neurons ( Cepeda et al . , 2010 ) . We hypothesized that these modifications would result in distinct EEG ' signatures ' that could be identified across the course of the dis - ease in R6 / 2 mice . We found dramatic alterations in quantitative EEG measures that included large increases in high frequency gamma activity and enhanced theta activity evident in non - REM "
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    ABSTRACT: Deficits in sleep and circadian organization have been identified as common early features in patients with Huntington's disease that correlate with symptom severity and may be instrumental in disease progression. Studies in Huntington's disease gene carriers suggest that alterations in the electroencephalogram may reflect underlying neuronal dysfunction that is present in the premanifest stage. We conducted a longitudinal characterization of sleep/wake and electroencephalographic activity in the R6/2 mouse model of Huntington's disease to determine whether analogous electroencephalographic 'signatures' could be identified early in disease progression. R6/2 and wild-type mice were implanted for electroencephalographic recordings along with telemetry for the continuous recording of activity and body temperature. Diurnal patterns of activity and core body temperature were progressively disrupted in R6/2 mice, with a large reduction in the amplitude of these rhythms apparent by 13 weeks of age. The diurnal variation in sleep/wake states was gradually attenuated as sleep became more fragmented and total sleep time was reduced relative to wild-type mice. These genotypic differences were augmented at 17 weeks and evident across the entire 24-h period. Quantitative electroencephalogram analysis revealed anomalous increases in high beta and gamma activity (25-60 Hz) in all sleep/wake states in R6/2 mice, along with increases in theta activity during both non-rapid eye movement and rapid eye movement sleep and a reduction of delta power in non-rapid eye movement sleep. These dramatic alterations in quantitative electroencephalographic measures were apparent from our earliest recording (9 weeks), before any major differences in diurnal physiology or sleep/wake behaviour occurred. In addition, the homeostatic response to sleep deprivation was greatly attenuated with disease progression. These findings demonstrate the sensitivity of quantitative electroencephalographic analysis to identify early pathophysiological alterations in the R6/2 model of Huntington's disease and suggest longitudinal studies in other preclinical Huntington's disease models are needed to determine the generality of these observations as a potential adjunct in therapeutic development.
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