title: Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington's disease and mouse models.
abstract: Cannabinoid receptor 1 (CB(1)  receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB(1)  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 CB(1)  signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB(1)  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 CB(1)  expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB(1)  is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)-expressing interneurons while remaining unchanged in parvalbumin- and calretinin-expressing interneurons. CB(1)  downregulation in striatal NPY/nNOS-expressing interneurons occurs in R6/2 mice, Hdh(Q150/Q150)  mice and the caudate nucleus of patients with HD. In R6/2 mice, CB(1)  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 CB(1)  signaling in NPY/nNOS-expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD.
authors.affiliation: Department of Pharmacology, University of Washington, 1959 N.E. Pacific St., Seattle, WA 98195-7280, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Horne
authors.forename: Jonathan
authors.initials: J
authors.lastname: Coy
authors.forename: Katie
authors.initials: K
authors.lastname: Swinney
authors.forename: Susan
authors.initials: S
authors.lastname: Fung
authors.forename: Allison E T
authors.initials: AE
authors.lastname: Cherry
authors.forename: William R
authors.initials: WR
authors.lastname: Marrs
authors.forename: Alipi V
authors.initials: AV
authors.lastname: Naydenov
authors.forename: Yi Hsing
authors.initials: YH
authors.lastname: Lin
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Sun
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.forename: Eric
authors.initials: E
authors.lastname: Grouzmann
authors.forename: Paul
authors.initials: P
authors.lastname: Muchowski
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001479:Basal Ganglia / Q000166:cytology / Q000378:metabolism*; D064032:Calbindin 2; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D016022:Case-Control Studies; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D007395:Interneurons / Q000145:classification / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C576764:CALB2 protein, human; C576511:Calb2 protein, mouse; D064032:Calbindin 2; D063386:Cannabinoid Receptor Agonists; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D009687:Nuclear Proteins; D010320:Parvalbumins; D043884:Receptor, Cannabinoid, CB1; D064030:S100 Calcium Binding Protein G; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase