Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington disease gene
Open accessAbstract
Loss of neurotransmitter receptors, especially glutamate and dopamine receptors, is one of the pathologic hallmarks of brains of patients with Huntington disease (HD). Transgenic mice that express exon 1 of an abnormal human HD gene (line R6/2) develop neurologic symptoms at 9–11 weeks of age through an unknown mechanism. Analysis of glutamate receptors (GluRs) in symptomatic 12-week-old R6/2 mice revealed decreases compared with age-matched littermate controls in the type 1 metabotropic GluR (mGluR1), mGluR2, mGluR3, but not the mGluR5 subtype of G protein-linked mGluR, as determined by [ 3 H]glutamate receptor binding, protein immunoblotting, and in situ hybridization. Ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors were also decreased, while N -methyl- d -aspartic acid receptors were not different compared with controls. Other neurotransmitter receptors known to be affected in HD were also decreased in R6/2 mice, including dopamine and muscarinic cholinergic, but not γ-aminobutyric acid receptors. D 1 -like and D 2 -like dopamine receptor binding was drastically reduced to one-third of control in the brains of 8- and 12-week-old R6/2 mice. In situ hybridization indicated that mGluR and D 1 dopamine receptor mRNA were altered as early as 4 weeks of age, long prior to the onset of clinical symptoms. Thus, altered expression of neurotransmitter receptors precedes clinical symptoms in R6/2 mice and may contribute to subsequent pathology.
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Mutant huntingtin aggregates could sequester proteins involved in synaptic transmission (such as PSD-95 and AMPA receptors) and lead to depletion of these proteins at their site of action.
“Mutant huntingtin aggregates could sequester proteins that are involved in synaptic transmission, such as the scaffolding protein PSD-95, and AMPA receptors among many others and lead to depletion of these proteins at their site of action (Cha et al., 1998;Sun et al., 2001;Luthi-Carter”
From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Cha et al., 1998
mRNA and protein levels of PSD-95 and AMPA receptors are reduced in HD patients and animal models.
“Interestingly, the mRNA and protein levels of PSD-95 and AMPA receptors are reduced in HD patients and in animal models (Cha et al., 1998;Sun et al., 2001;Luthi-Carter et al., 2003).”
From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Cha et al., 1998
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“…in synaptic transmission, such as the scaffolding protein PSD-95, and AMPA receptors among many others and lead to depletion of these proteins at their site of action (Cha et al., 1998; Sun et al., 2001; Luthi-Carter et al., 2003; Smith et al., 2005a,b, 2007; Nithianantharajah and Hannan, 2012).”
BackgroundLuthi-Carter, R., Apostol, B. L., Dunah, A. W., DeJohn, M. M., Farrell, L. A., Bates, G. P., Young, A. B., Standaert, D. G., Thompson, L. M., & Cha, J.-H. J. (2003) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.08.024 · Cited by 104 · see citing works
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- Authors
- Cha, J.-H. J., Kosinski, C. M., Kerner, J. A., Alsdorf, S. A., Mangiarini, L., Davies, S. W., Penney, J. B., Bates, G. P., & Young, A. B.
- Affiliations
- Guy's Hospital (GB)
- Corresponding author
- Young, Anne B.
- ORCID
- Bates, Gillian P.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-05-26
- Volume
- 95
- Issue
- 11
- Pages
- 6480-6485
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC27817
- OpenAlex
- W2170453612
- Cited by
- 504
- References
- 4
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 11 · 2020: 9 · 2019: 5 · 2018: 15 · 2017: 11 · 2016: 10 · 2015: 17 · 2014: 21 · 2013: 16 · 2012: 23
- FWCI
- 12.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Hereditary Disease Foundation
- Glendorn Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5k08ns001916-03, 5p01ns031579-05)
- U.S. Public Health Service (AG13617, NS31579)
- Medical Research Council
- National Institute on Aging (R01AG013617, R37AG013617, P01AG011337, AG11337)
- National Institute of Neurological Disorders and Stroke (NS31579, NS 01916)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Huntington's disease, R6/2 transgenic mice, neurotransmitter receptors, metabotropic glutamate receptors, mGluR1, mGluR2, mGluR3, mGluR5, dopamine receptors, dopamine D1 receptor, dopamine D2 receptor, glutamate receptors, kainate receptors, NMDA receptor, muscarinic receptors, GABA receptors, receptor mRNA expression
- MeSH terms
- Huntingtin Protein, Animals, Brain, Dopamine, Humans, Huntington Disease, Mice, Transgenic, Nerve Tissue Proteins, Nuclear Proteins, Radioligand Assay, Receptors, Dopamine, Transfection, Receptors, Glutamate, Glutamic Acid, Mice
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