VGLUT3 deletion rescues motor deficits and neuronal loss in the zQ175 mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by progressive motor and cognitive impairments, with no disease-modifying therapies yet available. HD pathophysiology involves evident impairment in glutamatergic neurotransmission leading to severe striatal neurodegeneration. The vesicular glutamate transporter-3 (VGLUT3) regulates the striatal network that is centrally affected by HD. Nevertheless, current evidence on the role of VGLUT3 in HD pathophysiology is lacking. Here, we crossed mice lacking gene ( ) with heterozygous knock-in mouse model of HD ( ). Longitudinal assessment of motor and cognitive functions from 6-15 months of age reveals that VGLUT3 deletion rescues motor coordination and short-term memory deficits in both male and female mice. VGLUT3 deletion also rescues neuronal loss likely via the activation of Akt and ERK1/2 in the striatum of mice of both sexes. Interestingly, the rescue in neuronal survival in mice is accompanied by a reduction in the number of nuclear mutant huntingtin (mHTT) aggregates with no change in the total aggregate levels or microgliosis. Collectively, these findings provide novel evidence that VGLUT3, despite its limited expression, can be a vital contributor to HD pathophysiology and a viable target for HD therapeutics.Dysregulation of the striatal network centrally contributes to the pathophysiology of Huntington's Disease (HD). The atypical vesicular glutamate transporter-3 (VGLUT3) has been shown to regulate several major striatal pathologies such as addiction, eating disorders, or L-DOPA-induced dyskinesia. Yet, our understanding of VGLUT3's role in HD remains unclear. We report here that deletion of the () gene rescues the deficits in both motor and cognitive functions in HD mice of both sexes. We also find that VGLUT3 deletion activates neuronal survival signaling and reduces nuclear aggregation of abnormal huntingtin proteins and striatal neuron loss in HD mice. Our novel findings highlight the vital contribution of VGLUT3 in HD pathophysiology that can be exploited for HD therapeutic management.