NMDA Receptor Losses in Putamen from Patients with Huntington's Disease

Young, A. Byron; Greenamyre, J. Timothy; Hollingsworth, Zane R.; Albin, Roger L.; D’Amato, Constance J.; Shoulson, Ira; Penney, JB

doi:10.1126/science.2841762

Cited by 376 publications

(142 citation statements)

References 41 publications

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“…These findings are in good accordance with human post-mortem studies (Glass et al 2000) that have been confirmed by in vivo PET studies, which clearly demonstrate a massive loss of D 2 dopamine (Turjanski et al 1995;Ginovart et al 1997;Antonini et al 1998;Araujo et al 2000;Pavese et al 2003) and A 2A adenosine (Ishiwata et al 2002) receptors, respectively. A reduction of NMDA receptor density, which has been described in the putamen of HD patients (Young et al 1988), could not be confirmed. Instead, we found a loss of NMDA receptor binding in the ventral striatum.…”

Section: Regional Pattern Of Receptor Changesmentioning

confidence: 68%

Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Bauer

Zilles

Matusch

et al. 2005

Journal of Neurochemistry

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Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder caused by a CAG/polyglutamine repeat expansion in the gene encoding the huntingtin protein. We have recently generated a rat model transgenic for HD, which displays a slowly progressive phenotype resembling the human adult-onset type of disease. In this study we systematically assessed the distribution and density of 17 transmitter receptors in the brains of 2-year-old rats using quantitative multi-tracer autoradiography and highresolution positron emission tomography. Heterozygous animals expressed increased densities of M 2 acetylcholine (increase of 148 ± 16% of controls; p > 0.001; n ¼ 7), nicotine (increase of 149 ± 16% of controls; p > 0.01; n ¼ 6), and a 2 noradrenergic receptors (increase of 141 ± 15% of controls; p > 0.001; n ¼ 6), respectively. Densities of these receptors were decreased in homozygous animals. Decreases of receptor density in both hetero-and homozygous animals were found for M 1 acetylcholine, 5-HT 2A serotonin, A 2A adenosine, D 1 and D 2 dopamine, and GABA A receptors, respectively. Other investigated receptor systems showed small changes or were not affected. The present data suggest that the moderate increase of CAG/polyglutamine repeat expansions in the present rat model of Huntington's disease is characterized by subtype-selective and region-specific changes of neuroreceptor densities. In particular, there is evidence for a contribution of predominantly presynaptically localized cholinergic and noradrenergic receptors in the response to Huntington's disease pathology.

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Section: Regional Pattern Of Receptor Changesmentioning

confidence: 68%

Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Bauer

Zilles

Matusch

et al. 2005

Journal of Neurochemistry

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“…Excitotoxicity has been implicated in the pathophysiology of various human brain disorders, including Alzheimer disease [9,10], Parkinson disease [11], Huntington disease [12], schizophrenia [13], and bipolar disorder [14][15][16]. Studies have demonstrated increased concentrations of glutamate and reduced levels of NMDA receptor (NR) subunits in the brain of some of these patients.…”

Section: Introductionmentioning

confidence: 99%

Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation

et al. 2008

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Chronic N-Methyl-D-aspartate (NMDA) administration, a model of excitotoxicity, and chronic intracerebroventricular lipopolysaccharide infusion, a model of neuroinflammation, are reported to upregulate arachidonic acid incorporation and turnover in rat brain phospholipids as well as enzymes involved in arachidonic acid metabolism. This suggests cross-talk between signaling pathways of excitotoxicity and of neuroinflammation, involving arachidonic acid. To test whether chronic NMDA administrations to rats can upregulate brain markers of neuroinflammation, NMDA (25 mg/kg i.p.) or vehicle (1 ml saline/kg i.p.) was administered daily to adult male rats for 21 days. Protein and mRNA levels of cytokines and other inflammatory markers were measured in the frontal cortex using immunoblot and real-time PCR. Compared with chronic vehicle, chronic NMDA significantly increased protein and mRNA levels of interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase. Chronic NMDA receptor overactivation results in increased levels of neuroinflammatory markers in the rat frontal cortex, consistent with cross-talk between excitotoxicity and neuroinflammation. As both processes have been reported in a number of human brain diseases, NMDA receptor inhibitors might be of use in treating neuroinflammation in these diseases.

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“…Intrastriatal injection of glutamate or kainic acid in rat causes selective loss of medium spiny neurons that are also selectively affected in HD (15). In the brains of HD patients, NMDA receptor-binding sites were disproportionately reduced even at the pre-symptomatic stage (16,17). In neuronal cells expressing the mutated huntingtin or mice transgenic for HD, NMDA receptors are highly responsive to the receptor agonists, and the receptor-mediated current is also significantly increased (18 -20).…”

mentioning

confidence: 99%

Expression of Polyglutamine-expanded Huntingtin Induces Tyrosine Phosphorylation of N-Methyl-D-aspartate Receptors

Song

Zhang

Parsons

et al. 2003

Journal of Biological Chemistry

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Huntington's disease (HD) 1 is a progressive neurodegenerative disorder with an autosomal dominant inheritance (2). The HD gene, encoding an ϳ350-kDa protein designated as huntingtin, is ubiquitously expressed (3,4). The genetic defect in the HD gene involves an expansion of a polyglutamine stretch near the 5Ј-end of the gene (5). The length of the polyglutamine repeat is correlated with the age of onset and the severity of the disease (6, 7).PSD-95, a scaffold protein, anchors many signaling proteins to the NMDA receptor complex and regulates biological function of the receptors (8,9). Tyrosine phosphorylation by the Src family is an important molecular mechanism for the regulation of the NMDA receptor function (10). Src tyrosine kinases are anchored by PSD-95 to the proximity of NMDA receptors where they induce tyrosine phosphorylation of NR2A and NR2B subunits and enhance the receptor-mediated current (10). Ischemic or inflammatory insults increase tyrosine phosphorylation of NMDA receptors at the PSD (post-synaptic density) fraction (11-13). Inhibition of the interaction of NMDA receptors with PSD-95 significantly attenuates ischemia-induced brain damage (14). These studies indicate that PSD-95 and tyrosine phosphorylation of NMDA receptors may be involved in excitotoxicity mediated by glutamate.Many studies have shown that increased glutamate-mediated excitotoxicity may play an important role in the pathogenesis of HD. Intrastriatal injection of glutamate or kainic acid in rat causes selective loss of medium spiny neurons that are also selectively affected in HD (15). In the brains of HD patients, NMDA receptor-binding sites were disproportionately reduced even at the pre-symptomatic stage (16,17). In neuronal cells expressing the mutated huntingtin or mice transgenic for HD, NMDA receptors are highly responsive to the receptor agonists, and the receptor-mediated current is also significantly increased (18 -20). In our previous studies, we observed that expression of polyglutamine-expanded huntingtin induced sensitization of NMDA receptor via PSD-95 (1). In the present studies, we examined whether tyrosine phosphorylation of NMDA receptors may contribute to the sensitization of the receptors in HN33 cells. We found that expression of the mutated huntingtin induced tyrosine phosphorylation of NMDA receptors, and inhibition of the phosphorylation attenuated the neuronal toxicity mediated by the mutated huntingtin in HN33 cells. MATERIALS AND METHODSCell Culture, Plasmids, Transfection, and Kinase Assays-Wild-type NR1 or NR2B expression vectors were provided by Dr. J. Marshall, and triply mutated NR2B and fyn vectors were provided by Dr. M. Greenberg (21). HN33 and 293T cells were maintained in F12/Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. We performed transient transfection using Lipofectin per instruction by the manufacturer. For detecting pSrc, HN33 or 293T cells were lysed with 1% Triton X-100 buffer (22) 24 h following the transfection. These cell lysates (30 g of protei...

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NMDA Receptor Losses in Putamen from Patients with Huntington's Disease

Cited by 376 publications

References 41 publications

Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation

Expression of Polyglutamine-expanded Huntingtin Induces Tyrosine Phosphorylation of N-Methyl-D-aspartate Receptors

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