title: Metabotropic glutamate receptor 5 knockout promotes motor and biochemical alterations in a mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein, which promotes progressive neuronal cell loss, neurological symptoms and death. In the present study, we show that blockade of mGluR5 with MTEP promotes increased locomotor activity in both control (Hdh(Q20/Q20)) and mutant HD (Hdh(Q111/Q111)) mice. Although acute injection of MTEP increases locomotor activity in both control and mutant HD mice, locomotor activity is increased in only control mice, not mutant HD mice, following the genetic deletion of mGluR5. Interestingly, treatment of mGluR5 knockout mice with either D1 or D2 dopamine antagonists eliminates the increased locomotor activity of mGluR5 knockout mice. Amphetamine treatment increases locomotor activity in control mice, but not mGluR5 null mutant HD mice. However, the loss of mGluR5 expression improves rotarod performance and decreases the number of huntingtin intranuclear inclusions in mutant HD mice. These adaptations may be due to mutant huntingtin-dependent alterations in gene expression, as microarray studies have identified several genes that are altered in mutant, but not wild-type HD mice lacking mGluR5 expression. qPCR experiments confirm that the mRNA transcript levels of dynein heavy chain, dynactin 3 and dynein light chain-6 are altered following the genetic deletion of mGluR5 in mutant HD mice, as compared with wild-type mutant HD mice. Thus, our data suggest that mutant huntingtin protein and mGluR5 exhibit a functional interaction that may be important for HD-mediated alterations in locomotor behavior and the development of intranuclear inclusions.
authors.affiliation: Departamento de Bioquimica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
authors.forename: Fabiola M
authors.initials: FM
authors.lastname: Ribeiro
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Devries
authors.forename: Alison
authors.initials: A
authors.lastname: Hamilton
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Guimaraes
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cregan
authors.forename: Rita G W
authors.initials: RG
authors.lastname: Pires
authors.forename: Stephen S G
authors.initials: SS
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C578936:Grm5 protein, mouse; D011725:Pyridines; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D013844:Thiazoles