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.

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

“…It seems likely, therefore, that increased activity in the direct pathway is in part responsible for chorea-like symptoms. In agreement with this view, targeted ablation of striatal D 1 receptors in mice is sufficient to cause gait disturbances and involuntary movements [258]. In addition, optogenetic approaches have revealed that selective activation of the striatonigral pathway is directly involved not only in movement initiation but also in motor action sequences [66, 173].…”

Dysfunctional striatal dopamine signaling in Huntington's disease

“…Increased levels of downstream signaling targets of D1 receptors in HD mice provide further evidence of elevated D1 signaling in HD (Ariano et al, ; Fusco et al, ; Roze et al, ; Spektor et al, ). Alternatively, the loss of D1 receptor‐expressing SPNs has been associated with HD symptoms as well: post‐natal ablation of dSPNs in mice results in a variety of motor symptoms including reduced locomotion, irregular gait, and tic‐like movements (Kim et al, ).…”

Animal models of tic disorders: A translational perspective

“…Based on the well-documented striatal disinhibition in TS (Baym et al, 2008; Mazzone et al, 2010; Wang et al, 2011; Bronfeld et al, 2013) and the finding of a selective loss in parvalbumin-positive interneurons in the striatum of TS patients (Kalanithi et al, 2005; Kataoka et al, 2010), a number of studies have begun addressing direct neurobiological hypotheses by producing selective lesions and/or pharmacological treatments in the basal ganglia. Remarkably, selective ablation of D 1 -receptor expressing striatal neurons has recently been shown to exhibit tic-like movements sensitive to treatment with the dopaminergic blocker haloperidol, as well as other locomotor impairments and striatal atrophy (Kim et al, 2014). …”