Article

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.

Download full-text

Full-text

Available from: Carlos Cepeda, Jul 10, 2015
0 Followers
 · 
109 Views
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging is accompanied by reduced regenerative capacity of all tissues and organs and dysfunction of adult stem cells. Notably, these age-related alterations contribute to distinct pathophysiological characteristics depending on the tissue of origin and function and thus require special attention in a type by type manner. In this paper, we review the current understanding of the mechanisms leading to tissue-specific adult stem cell dysfunction and reduced regenerative capacity with age. A comprehensive investigation of the hematopoietic, the neural, the mesenchymal, and the skeletal stem cells in age-related research highlights that distinct mechanisms are associated with the different types of tissue stem cells. The link between age-related stem cell dysfunction and human pathologies is discussed along with the challenges and the future perspectives in stem cell-based therapies in age-related diseases.
    Biogerontology 10/2013; 14(6). DOI:10.1007/s10522-013-9469-9 · 3.01 Impact Factor
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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.
    Brain 07/2013; 136(Pt 7):2159-2172. DOI:10.1093/brain/awt132 · 10.23 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Impairment of energy metabolism is a key feature of Huntington disease (HD). Recently, we reported longitudinal neurochemical changes in R6/2 mice measured by in-vivo proton magnetic resonance spectroscopy ((1)H MRS; Zacharoff et al, 2012). Here, we present similar (1)H MRS measurements at an early stage in the milder Q111 mouse model. In addition, we measured the concentration of ATP and inorganic phosphate (P(i)), key energy metabolites not accessible with (1)H MRS, using (31)P MRS both in Q111 and in R6/2 mice. Significant changes in striatal creatine and phosphocreatine were observed in Q111 mice at 6 weeks relative to control, and these changes were largely reversed at 13 weeks. No significant change was detected in ATP concentration, in either HD mouse, compared with control. Calculated values of [ADP], phosphorylation potential, relative rate of ATP synthase (v/V(max)(ATP)), and relative rate of creatine kinase (v/V(max)(CK)) were calculated from the measured data. ADP concentration and v/V(max)(ATP) were increased in Q111 mice at 6 weeks, and returned close to normal at 13 weeks. In contrast, these parameters were normal in R6/2 mice. These results suggest that early changes in brain energy metabolism are followed by compensatory shifts to maintain energetic homeostasis from early ages through manifest disease.Journal of Cerebral Blood Flow & Metabolism advance online publication, 18 July 2012; doi:10.1038/jcbfm.2012.104.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2012; 32(11). DOI:10.1038/jcbfm.2012.104 · 5.34 Impact Factor
Show more