title: Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice.
abstract: Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.
authors.affiliation: 1] Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2].
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Tong
authors.affiliation: 1] Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2].
authors.forename: Yan
authors.initials: Y
authors.lastname: Ao
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Guido C
authors.initials: GC
authors.lastname: Faas
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Sinifunanya E
authors.initials: SE
authors.lastname: Nwaobi
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Haustein
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Anderson
authors.affiliation: 1] Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Mody
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Olsen
authors.affiliation: 1] Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2].
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sofroniew
authors.affiliation: 1] Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [3].
authors.forename: Baljit S
authors.initials: BS
authors.lastname: Khakh
mesh_terms: D000367:Age Factors; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D003342:Corpus Striatum / Q000503:physiopathology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D019417:Hindlimb Suspension / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D066298:In Vitro Techniques; D008124:Locomotion / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency* / Q000235:genetics; D016019:Survival Analysis; D018911:Trinucleotide Repeats / Q000235:genetics; D000098854:Kcnj10 Channel
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D000098854:Kcnj10 Channel; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D024661:Potassium Channels, Inwardly Rectifying; D049452:Green Fluorescent Proteins