Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington's disease and mouse models

Cannabinoid receptor 1 (CB1 receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB1 expression in the basal ganglia of patients with Huntington's disease (HD) and animal models represen...

Full description

Saved in:

Bibliographic Details
Published in:	The European journal of neuroscience Vol. 37; no. 3; pp. 429 - 440
Main Authors:	Horne, Eric A., Coy, Jonathan, Swinney, Katie, Fung, Susan, Cherry, Allison E. T., Marrs, William R., Naydenov, Alipi V., Lin, Yi Hsing, Sun, Xiaocui, Dirk Keene, C., Grouzmann, Eric, Muchowski, Paul, Bates, Gillian P., Mackie, Ken, Stella, Nephi
Format:	Journal Article
Language:	English
Published:	Oxford Blackwell Publishing Ltd 01-02-2013 Blackwell
Subjects:	Adult Adult and adolescent clinical studies Aged Animal models Animals Basal ganglia Basal Ganglia - cytology Basal Ganglia - metabolism Biological and medical sciences Calbindin 2 Cannabinoid CB1 receptors Cannabinoid Receptor Agonists - pharmacology Case-Control Studies Caudate nucleus CB 1 CB1 CREB Cyclic AMP - metabolism Cyclic AMP response element-binding protein Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Models, Animal Down-Regulation Female gamma -Aminobutyric acid Gene Expression Humans Huntingtin Huntington Disease - metabolism Huntington's disease Immunohistochemistry Interneurons Interneurons - classification Interneurons - metabolism Male Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Neostriatum Nerve Tissue Proteins - genetics Nervous system (semeiology, syndromes) Nervous system as a whole neurodegeneration Neurology Neuropeptide Y Neuropeptide Y - genetics Neuropeptide Y - metabolism Neuropharmacology Neurotransmitter release Nitric Oxide Synthase - genetics Nitric Oxide Synthase - metabolism Nitric-oxide synthase NPY Nuclear Proteins - genetics Organic mental disorders. Neuropsychology Parvalbumins - genetics Parvalbumins - metabolism Pharmacology. Drug treatments Phosphorylation Plasticity (synaptic) Psychodysleptics: hallucinogen Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Psychopharmacology R6/2 Receptor, Cannabinoid, CB1 - agonists Receptor, Cannabinoid, CB1 - genetics Receptor, Cannabinoid, CB1 - metabolism S100 Calcium Binding Protein G - genetics S100 Calcium Binding Protein G - metabolism Serotonin Plasma Membrane Transport Proteins - genetics Serotonin Plasma Membrane Transport Proteins - metabolism Signal transduction spiny neurons Animal model Central nervous system neurodegeneration Neuropeptide Y receptor Encephalon Interneuron CREB Cannabinoid receptor NPY Degenerative disease Degeneration Transcription factor CREB CB Human Neuropeptide Y R6/2 Nervous system diseases Rodentia Huntington disease Basal ganglion Genetic disease Cerebral disorder Vertebrata Mammalia Mouse Animal Central nervous system disease Extrapyramidal syndrome
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Cannabinoid receptor 1 (CB1 receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB1 expression in the basal ganglia of patients with Huntington's disease (HD) and animal models represents one of the earliest molecular events induced by mutant huntingtin (mHtt). This early disruption of neuronal CB1 signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB1 downregulation measured in patients with HD and mouse models was ubiquitous or restricted to specific striatal neuronal subpopulations. Using unbiased semi‐quantitative immunohistochemistry, we confirmed previous studies showing that CB1 expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB1 is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)‐expressing interneurons while remaining unchanged in parvalbumin‐ and calretinin‐expressing interneurons. CB1 downregulation in striatal NPY/nNOS‐expressing interneurons occurs in R6/2 mice, HdhQ150/Q150 mice and the caudate nucleus of patients with HD. In R6/2 mice, CB1 downregulation in NPY/nNOS‐expressing interneurons correlates with diffuse expression of mHtt in the soma. This downregulation also occludes the ability of cannabinoid agonists to activate the pro‐survival signaling molecule cAMP response element‐binding protein in NPY/nNOS‐expressing interneurons. Loss of CB1 signaling in NPY/nNOS‐expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD. Cannabinoid Receptor 1 (CB1 receptor) regulates several neuronal functions, including neurotransmitter release and neuronal viability, and is one of the earliest down‐regulated proteins in Huntington's disease (HD). We show here that of CB1 receptor expression is down‐regulated in both indirect pathway medium spiny neurons and NPY/nNOS+ interneurons in the striatum of HD mouse models and patients. CB1 receptor down‐regulation in NPY/nNOS+ interneurons correlates with the presence of micro‐aggregates of mutant huntingtin protein, and prevents cannabinoid mediated CREB phosphorylation in NPY/nNOS+ interneurons. CB1 receptor loss at NPY/nNOS+ interneurons could contribute to the altered GABAergic signaling present in the striatum of HD patients and ultimately to the pathogenesis of HD.
Bibliography:	ArticleID:EJN12045 ark:/67375/WNG-81BTB7DV-D istex:AC859C96A49A8C7FFBE2051CA8DA214DF89FDA93 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0953-816X 1460-9568
DOI:	10.1111/ejn.12045