The corticostriatal pathway in Huntington’s disease. Prog Neurobiol

Mental Retardation Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Progress in Neurobiology (Impact Factor: 9.99). 05/2007; 81(5-6):253-71. DOI: 10.1016/j.pneurobio.2006.11.001
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The corticostriatal pathway provides most of the excitatory glutamatergic input into the striatum and it plays an important role in the development of the phenotype of Huntington's disease (HD). This review summarizes results obtained from genetic HD mouse models concerning various alterations in this pathway. Evidence indicates that dysfunctions of striatal circuits and cortical neurons that make up the corticostriatal pathway occur during the development of the HD phenotype, well before there is significant neuronal cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium-sized spiny neurons. Some of these alterations, including increased sensitivity of N-methyl-D-aspartate receptors in subpopulations of neurons, might be constitutively present but ultimately require abnormalities in the corticostriatal inputs for the phenotype to be expressed. Dysfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. The conclusions of this review emphasize, first, the general role of neuronal circuits in the expression of the HD phenotype and, second, that both cortical and striatal circuits must be included in attempts to establish a framework for more rational therapeutic strategies in HD. Finally, as changes in cortical and striatal circuitry are complex and in some cases biphasic, therapeutic interventions should be regionally specific and take into account the temporal progression of the phenotype.

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Available from: Carlos Cepeda, Oct 05, 2015
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    • "I N T R O D U C T I O N Huntington's disease (HD) is a monogenetic neurodegenerative disorder associated with characteristic hyperkinetic motoric dysfunction (chorea) accompanied by cognitive and emotional deficits (Cepeda et al., 2007; Imarisio et al., 2008; Miller and Bezprozvanny, 2010). The disease is of autosomal dominant inheritance and results from an expanded CAG triplet repeat in exon 1 of the gene coding for huntingtin (htt), a 348-kD soluble globular protein. "
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    ABSTRACT: Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat within the gene encoding the protein huntingtin. The resulting elongated glutamine (poly-Q) sequence of mutant huntingtin (mhtt) affects both central neurons and skeletal muscle. Recent reports suggest that ryanodine receptor-based Ca(2+) signaling, which is crucial for skeletal muscle excitation-contraction coupling (ECC), is changed by mhtt in HD neurons. Consequently, we searched for alterations of ECC in muscle fibers of the R6/2 mouse, a mouse model of HD. We performed fluorometric recordings of action potentials (APs) and cellular Ca(2+) transients on intact isolated toe muscle fibers (musculi interossei), and measured L-type Ca(2+) inward currents on internally dialyzed fibers under voltage-clamp conditions. Both APs and AP-triggered Ca(2+) transients showed slower kinetics in R6/2 fibers than in fibers from wild-type mice. Ca(2+) removal from the myoplasm and Ca(2+) release flux from the sarcoplasmic reticulum were characterized using a Ca(2+) binding and transport model, which indicated a significant reduction in slow Ca(2+) removal activity and Ca(2+) release flux both after APs and under voltage-clamp conditions. In addition, the voltage-clamp experiments showed a highly significant decrease in L-type Ca(2+) channel conductance. These results indicate profound changes of Ca(2+) turnover in skeletal muscle of R6/2 mice and suggest that these changes may be associated with muscle pathology in HD.
    The Journal of General Physiology 11/2014; 144(5):393-413. DOI:10.1085/jgp.201411255 · 4.79 Impact Factor
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    • "This preferential innervation is believed to release more glutamate which could contribute to make D2 MSNs more vulnerable to excitotoxicity (Reiner et al., 2003; Ballion et al., 2008). Many electrophysiological evidences suggest that D2 MSNs are more excitable than D1 MSNs (Cepeda et al., 2007; Kreitzer and Malenka, 2007) partly because they display fewer primary dendrites (Gertler et al., 2008). Electrophysiological recordings of D2 MSNs show a higher frequency of spontaneous excitatory post-synaptic currents (sEP- SCs) than direct pathway. "
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    ABSTRACT: HD is caused by a mutation in the huntingtin gene that consists in a CAG repeat expansion translated into an abnormal poly-glutamine (polyQ) tract in the huntingtin (Htt) protein. The most striking neuropathological finding in HD is the atrophy of the striatum. The regional expression of mutant Htt (mHtt) is ubiquitous in the brain and cannot explain by itself the preferential vulnerability of the striatum in HD. mHtt has been shown to produce an early defect in transcription, through direct alteration of the function of key regulators of transcription and in addition, more indirectly, as a result of compensatory responses to cellular stress. In this review, we focus on gene products that are preferentially expressed in the striatum and have down- or up-regulated expression in HD and, as such, may play a crucial role in the susceptibility of the striatum to mHtt. Many of these striatal gene products are for a vast majority down-regulated and more rarely increased in HD. Recent research shows that some of these striatal markers have a pro-survival/neuroprotective role in neurons (e.g., MSK1, A2A, and CB1 receptors) whereas others enhance the susceptibility of striatal neurons to mHtt (e.g., Rhes, RGS2, D2 receptors). The down-regulation of these latter proteins may be considered as a potential self-defense mechanism to slow degeneration. For a majority of the striatal gene products that have been identified so far, their function in the striatum is unknown and their modifying effects on mHtt toxicity remain to be experimentally addressed. Focusing on these striatal markers may contribute to a better understanding of HD pathogenesis, and possibly the identification of novel therapeutic targets.
    Frontiers in Cellular Neuroscience 09/2014; 8:295. DOI:10.3389/fncel.2014.00295 · 4.29 Impact Factor
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    • "Other proteins that pathologically increase in the mitochondria cause excessive fragmentation and abnormal distribution in the cell (Reddy and Shirendeb 2012). There is coinciding loss of neurotrophic support with loss of connectivity between the cortex and striatum, affecting the anterograde transport of BDNF from the cortex to MSNs (Cepeda et al. 2007). This is observed as BDNF expression is decreased in the cortex and its receptor (TrkB) is decreased in the striatum (Zuccato and Cattaneo 2007). "
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    ABSTRACT: Huntington's Disease (HD) is one of many neurodegenerative diseases with reported alterations in brain iron homeostasis that may contribute to neuropathogenesis. Iron accumulation in the specific brain areas of neurodegeneration in HD has been proposed based on observations in post-mortem tissue and magnetic resonance imaging (MRI) studies. Altered MRI signal within specific brain regions undergoing neurodegeneration has been consistently reported and interpreted as altered levels of brain iron. Biochemical studies using various techniques to measure iron species in human samples, mouse tissue, or in vitro has generated equivocal data to support such an association. Whether elevated brain iron occurs in HD, plays a significant contributing role in HD pathogenesis, or is a secondary effect is currently unclear.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 04/2014; 130(3). DOI:10.1111/jnc.12739 · 4.28 Impact Factor
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