Age-Dependent Biphasic Changes in Ischemic Sensitivity in the Striatum of Huntington's Disease R6/2 Transgenic Mice

University of California, Los Angeles, Los Ángeles, California, United States
Journal of Neurophysiology (Impact Factor: 2.89). 03/2005; 93(2):758-65. DOI: 10.1152/jn.00483.2004
Source: PubMed


We used the oxygen/glucose deprivation (OGD) model of ischemia in corticostriatal brain slices to test the hypothesis that metabolic deficiencies in R6/2 transgenic Huntington's disease (HD) mice will impair their recovery from an ischemic challenge. Corticostriatal extracellular field excitatory postsynaptic potentials (fEPSPs) were evoked in transgenic and wild-type (WT) mice in three age groups: 3-4 wk, before the overt behavioral phenotype develops; 5-9 wk, as overt behavioral symptoms begin; and 10-15 wk when symptoms were most severe. OGD for 8 min completely and reversibly inhibited fEPSPs. Although responses of 3-4 wk WTs showed a tolerance to ischemia and recovered rapidly, ischemic sensitivity developed progressively; at 5-9 and 10-15 wk, responses recovered more slowly from OGD. In contrast, although 3-4 wk R6/2 transgenic fEPSPs showed significantly more ischemic sensitivity than their WT counterparts, the R6/2 fEPSPs maintained a relative tolerance to ischemia at 5-9 and 10-15 wk. As a result, a "crossover" point occurred, roughly coinciding with the development of the overt behavioral phenotype (5-9 wk), after which time R6/2 fEPSPs were significantly more resistant to ischemia than WT responses. The increased ischemic sensitivity in 3-4 wk R6/2 responses was not due to excessive glutamate release during OGD as it persisted in the presence of the glutamate receptor antagonist kynurenic acid (1 mM). Although the mechanism for development of ischemic resistance in R6/2 transgenics remains unknown, it correlates with metabolic and biochemical changes described in this model and in HD patients.

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Available from: Gloria J Klapstein,
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    • "Alternatively, the resistance phenomenon may be similar to pre-conditioning, as observed with ischemia, where permanent exposure to low levels of excitotoxicity and to changes in intracellular Ca 2+ homeostasis allows neurons to adapt to an even greater excitotoxic insult and sudden increase in intracellular Ca 2+ concentration. Accordingly, while corticostriatal brain slices from presymptomatic R6 ⁄ 2 mice showed an increased sensitivity to an ischemic insult (oxygen and glucose deprivation), slices derived from symptomatic and late-stage R6 ⁄ 2 mice were shown to be resistant to ischemia (Klapstein & Levine, 2005). Despite these controversial results, the striatum receives excitatory glutamatergic inputs from the entire cerebral cortex and the selective vulnerability displayed by striatal neurons in HD may be due to the vast glutamatergic inputs they receive and ⁄ or the particular types of glutamate receptors expressed in these cells. "
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    ABSTRACT: Huntington’s disease (HD) is caused by an expansion of cytosine–adenine–guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss in the striatum and cortex and to the appearance of neuronal intranuclear inclusions of mutant huntingtin. Huntingtin plays a role in protein trafficking, vesicle transport, postsynaptic signaling, transcriptional regulation, and apoptosis. Thus, a loss of function of the normal protein and a toxic gain of function of the mutant huntingtin contribute to the disruption of multiple intracellular pathways. Furthermore, excitotoxicity, dopamine toxicity, metabolic impairment, mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy have been implicated in the progressive degeneration observed in HD. Nevertheless, despite the efforts of a multidisciplinary scientific community, there is no cure for this devastating neurodegenerative disorder. This review presents an overview of the mechanisms that may contribute for HD pathogenesis. Ultimately, a better understanding of these mechanisms will lead to the development of more effective therapeutic targets.
    European Journal of Neuroscience 05/2008; 27(11):2803 - 2820. DOI:10.1111/j.1460-9568.2008.06310.x · 3.18 Impact Factor
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    • "In a recent study , we showed that striatal field potentials of 3 – 4 week R6 / 2 transgenic mice show significantly more sensitivity to ischemic challenge than do their WT counterparts . However , the R6 / 2 responses do not become more sensitive over age but rather maintain a relative tolerance to ischemia compared to controls ( Klapstein and Levine , 2005 ) . Metabolic deficiencies could explain increased sensitivity to ischemia in presymptomatic mice , but compensatory mechanisms may take place in striatal neurons to induce ischemic tolerance . "
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    ABSTRACT: 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.
    Progress in Neurobiology 05/2007; 81(5-6):253-71. DOI:10.1016/j.pneurobio.2006.11.001 · 9.99 Impact Factor
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