title: Real-time imaging of glutamate clearance reveals normal striatal uptake in Huntington disease mouse models.
abstract: It has become well accepted that Huntington disease (HD) is associated with impaired glutamate uptake, resulting in a prolonged time-course of extracellular glutamate that contributes to excitotoxicity. However, the data supporting this view come largely from work in synaptosomes, which may overrepresent nerve-terminal uptake over astrocytic uptake. Here, we quantify real-time glutamate dynamics in HD mouse models by high-speed imaging of an intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) and electrophysiological recordings of synaptically activated transporter currents in astrocytes. These techniques reveal a disconnect between the results obtained in synaptosomes and those in situ. Exogenous glutamate uptake is impaired in synaptosomes, whereas real-time measures of glutamate clearance in the HD striatum are normal or even accelerated, particularly in the aggressive R6/2 model. Our results highlight the importance of quantifying glutamate dynamics under endogenous release conditions, and suggest that the widely cited uptake impairment in HD does not contribute to pathogenesis.
authors.affiliation: Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Parsons
authors.affiliation: Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Matthieu P
authors.initials: MP
authors.lastname: Vanni
authors.affiliation: Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Cameron L
authors.initials: CL
authors.lastname: Woodard
authors.affiliation: Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Rujun
authors.initials: R
authors.lastname: Kang
authors.affiliation: Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Murphy
authors.affiliation: Brain Research Centre and Djavad Mowafaghian Centre for Brain Health, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D017930:Genes, Reporter; D005822:Genetic Vectors; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D061848:Optical Imaging / Q000379:methods*; D013569:Synapses / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D018698:Glutamic Acid