title: Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene.
abstract: 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 [3H]glutamate receptor binding, protein immunoblotting, and in situ hybridization. Ionotropic alpha-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 gamma-aminobutyric acid receptors. D1-like and D2-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 D1 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.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Cha
authors.forename: C M
authors.initials: CM
authors.lastname: Kosinski
authors.forename: J A
authors.initials: JA
authors.lastname: Kerner
authors.forename: S A
authors.initials: SA
authors.lastname: Alsdorf
authors.forename: L
authors.initials: L
authors.lastname: Mangiarini
authors.forename: S W
authors.initials: SW
authors.lastname: Davies
authors.forename: J B
authors.initials: JB
authors.lastname: Penney
authors.forename: G P
authors.initials: GP
authors.lastname: Bates
authors.forename: A B
authors.initials: AB
authors.lastname: Young
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics*; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000096:biosynthesis*; D017470:Receptors, Glutamate / Q000096:biosynthesis*; D014162:Transfection
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011954:Receptors, Dopamine; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D004298:Dopamine