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: 4.44). 05/2010; 2(2):e00033. DOI: 10.1042/AN20090058
Source: PubMed

ABSTRACT 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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Available from: Carlos Cepeda, Jul 10, 2015
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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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    • "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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    • "Oxidative stress, associated with development of the Huntington phenotype, activates PARP, resulting in NADH cycling and ATP depletion (Altmann et al, 2006). Increased demand could result from increased signaling and maintenance of ionic gradients accompanying electrophysiological changes (Cepeda et al, 2010). Elevation of NMDA receptor stimulated influx of intracellular calcium has also been postulated to increase cellular metabolic load (Fernandes et al, 2007). "
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