Resolving pathobiological mechanisms relating to Huntington disease: Gait, balance, and involuntary movements in mice with targeted ablation of striatal D1 dopamine receptor cells

Neurobiology of Disease

Ilse Gantois¹  Andrew J. Lawrence²  Clare L. Parish³  Colm O'Tuathaigh³  Hyun Ah. Kim³  Luning Jiang³  Jim Massalas³  Arthur Smardencas³  Heather Madsen³  John Drago³  Claire O'Leary³  Michelle E. Ehrlich⁴  John L. Waddington⁴ 

[1] Molecular and Cellular Therapeutics, RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland;Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA;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;

关键词: D1 dopamine receptor;    Huntington disease;    Striatum;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown