title: Resolving pathobiological mechanisms relating to Huntington disease: gait, balance, and involuntary movements in mice with targeted ablation of striatal D1 dopamine receptor cells.
abstract: Progressive cell loss is observed in the striatum, cerebral cortex, thalamus, hypothalamus, subthalamic nucleus and hippocampus in Huntington disease. In the striatum, dopamine-responsive medium spiny neurons are preferentially lost. Clinical features include involuntary movements, gait and orofacial impairments in addition to cognitive deficits and psychosis, anxiety and mood disorders. We utilized the Cre-LoxP system to generate mutant mice with selective postnatal ablation of D1 dopamine receptor-expressing striatal neurons to determine which elements of the complex Huntington disease phenotype relate to loss of this neuronal subpopulation. Mutant mice had reduced body weight, locomotor slowing, reduced rearing, ataxia, a short stride length wide-based erratic gait, impairment in orofacial movements and displayed haloperidol-suppressible tic-like movements. The mutation was associated with an anxiolytic profile. Mutant mice had significant striatal-specific atrophy and astrogliosis. D1-expressing cell number was reduced throughout the rostrocaudal extent of the dorsal striatum consistent with partial destruction of the striatonigral pathway. Additional striatal changes included up-regulated D2 and enkephalin mRNA, and an increased density of D2 and preproenkephalin-expressing projection neurons, and striatal neuropeptide Y and cholinergic interneurons. These data suggest that striatal D1-cell-ablation alone may account for the involuntary movements and locomotor, balance and orofacial deficits seen not only in HD but also in HD phenocopy syndromes with striatal atrophy. Therapeutic strategies would therefore need to target striatal D1 cells to ameliorate deficits especially when the clinical presentation is dominated by a bradykinetic/ataxic phenotype with involuntary movements.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Kim
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Luning
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Madsen
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Parish
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Jim
authors.initials: J
authors.lastname: Massalas
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Smardencas
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia; Molecular and Cellular Therapeutics, RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: O'Leary
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Ilse
authors.initials: I
authors.lastname: Gantois
authors.affiliation: Molecular and Cellular Therapeutics, RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Colm
authors.initials: C
authors.lastname: O'Tuathaigh
authors.affiliation: Molecular and Cellular Therapeutics, RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Ehrlich
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia. Electronic address: john.drago@florey.edu.au.
authors.forename: John
authors.initials: J
authors.lastname: Drago
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D020820:Dyskinesias / Q000503:physiopathology; D005260:Female; D005684:Gait / Q000502:physiology; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D004856:Postural Balance / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C583261:Drd1 protein, mouse; D017447:Receptors, Dopamine D1
keywords: D1 dopamine receptor; Huntington disease; Striatum