Impaired Glutamate Uptake in the R6 Huntington's Disease Transgenic Mice

Liévens, Jean-Charles; Woodman, Benjamin; Mahal, Amarbirpal; Spasic-Boscovic, O.; Samuel, D.; Goff, Lydia Kerkerian‐Le; Bates, Gillian P.

doi:10.1006/nbdi.2001.0430

Cited by 271 publications

(227 citation statements)

References 63 publications

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“…Dysfunction of astrocyte glutamate transport systems can lead to excitotoxic cell death due to excess extracellular glutamate (32). In the R6 transgenic mouse models of HD, mutant huntingtin accumulates in glial cells in association with reduced expression of glutamate transporters, decreased glutamate uptake, and excitotoxic neuronal death (33,34).…”

Section: Discussionmentioning

confidence: 99%

Selective defect of in vivo glycolysis in early Huntington's disease striatum

Powers

Videen

Markham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

152

153

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Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntington's disease (HD) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO2/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO2/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 ؎ 1.6 vs. 5.1 ؎ 0.9, P ‫؍‬ 0.04). CMRO2 was not different from controls (126 ؎ 37 vs. 134 ؎ 31 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.49), whereas CMRglc was decreased (21.6 ؎ 6.1 vs. 26.4 ؎ 4.6 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.01). Striatal volume was decreased as well (13.9 ؎ 3.5 vs. 17.6 ؎ 2.0 ml, P ‫؍‬ 0.001). Increased striatal CMRO2/CMRglc with unchanged CMRO2 is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HD. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HD.cerebral metabolism ͉ mitochondria ͉ oxidative phosphorylation ͉ basal ganglia H untington's disease (HD) is a degenerative neurological disease that is manifested by abnormal involuntary movements, psychiatric disorders, and dementia. It has a variable age at onset and progresses slowly to death 15-25 years after symptoms develop. HD is neuropathologically characterized by early selective loss of medium spiny neurons in striatum (caudate and putamen) with later neuronal loss in cortex, globus pallidus, and other structures. Although it is now known that an expansion of the triple repeat CAG in the IT15 gene on chromosome 4 leads to production of an abnormal polyglutamine string on the huntingtin protein, it is still unclear how this leads to selective neuronal cell death (1). In postmortem specimens from the striatum of patients with HD, reduced activity of the mitochondrial electron transport system (ETS) (29-76% decreases in complexes II and III and 30-62% decreases in complex IV) has been measured in vitro, although these findings have not been universal (2-6). These findings and the correlative effects of mitochondrial toxins in producing striatal neuronal loss in animal models suggest that excitotoxicity triggered by reduced ATP production as a consequence of impaired mitochondrial oxidative phosphorylation may be an important mechanism for neuronal death in HD (7). Alternatively, these mitochondrial changes may be ...

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Section: Discussionmentioning

confidence: 99%

Selective defect of in vivo glycolysis in early Huntington's disease striatum

Powers

Videen

Markham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

152

153

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“…Impaired glutamate uptake has been reported in transgenic rodent models of HD, but the effect of this on motor function has not been determined [176]. Dopamine transporter availability is significantly lower in patients exhibiting symptoms of PD [177].…”

Section: Cbd Transporter Targets In Movement Disordersmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…This work confirmed the results of a similar study that showed that GLT1 mRNA is decreased to about 30% of normal levels in both the striatum and cortex of huntingtin mutant mice. 114 …”

Section: Hypoxia/ischemiamentioning

confidence: 99%

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

Lauriat

McInnes

2007

Mol Psychiatry

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The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake in the brain and its dysregulation has been associated with multiple psychiatric and neurological disorders. However, investigation of this molecule has been complicated by its complex pattern of alternative splicing, including three coding isoforms and multiple 5 0 -and 3 0 -UTRs that may have a regulatory function. It is likely that these sequences permit modulation of EAAT2 expression with spatial, temporal and or activity-dependent specificity; however, few studies have attempted to delineate the function of these sequences. Additionally, there are problems with the use of antibodies to study protein localization, possibly due to posttranslational modification of critical amino acid residues. This review describes what is currently known about the regulation of EAAT2 mRNA and protein isoforms and concludes with a summary of studies showing dysregulation of EAAT2 in psychiatric and neurological disorders. EAAT2 has been either primarily or secondarily implicated in a multitude of neuropsychiatric diseases in addition to the normal physiology of learning and memory. Thus, this molecule represents an intriguing therapeutic target once we improve our understanding of how it is regulated under normal conditions.

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Impaired Glutamate Uptake in the R6 Huntington's Disease Transgenic Mice

Cited by 271 publications

References 63 publications

Selective defect of in vivo glycolysis in early Huntington's disease striatum

Selective defect of in vivo glycolysis in early Huntington's disease striatum

Molecular Targets of Cannabidiol in Neurological Disorders

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

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