title: Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.
abstract: Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a poly-glutamine (poly-Q) stretch in the huntingtin (Htt) protein. Gain-of-function effects of mutant Htt have been extensively investigated as the major driver of neurodegeneration in HD. However, loss-of-function effects of poly-Q mutations recently emerged as potential drivers of disease pathophysiology. Early synaptic problems in the excitatory cortical and striatal connections have been reported in HD, but the role of Htt protein in synaptic connectivity was unknown. Therefore, we investigated the role of Htt in synaptic connectivity in vivo by conditionally silencing Htt in the developing mouse cortex. When cortical Htt function was silenced, cortical and striatal excitatory synapses formed and matured at an accelerated pace through postnatal day 21 (P21). This exuberant synaptic connectivity was lost over time in the cortex, resulting in the deterioration of synapses by 5 weeks. Synaptic decline in the cortex was accompanied with layer- and region-specific reactive gliosis without cell loss. To determine whether the disease-causing poly-Q mutation in Htt affects synapse development, we next investigated the synaptic connectivity in a full-length knock-in mouse model of HD, the zQ175 mouse. Similar to the cortical conditional knock-outs, we found excessive excitatory synapse formation and maturation in the cortices of P21 zQ175, which was lost by 5 weeks. Together, our findings reveal that cortical Htt is required for the correct establishment of cortical and striatal excitatory circuits, and this function of Htt is lost when the mutant Htt is present.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Spencer U
authors.identifier: http://orcid.org/0000-0002-3704-8919
authors.initials: SU
authors.lastname: McKinstry
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Yonca B
authors.initials: YB
authors.lastname: Karadeniz
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Atesh K
authors.initials: AK
authors.lastname: Worthington
authors.affiliation: Department of Psychology and Neuroscience, Faculty of Arts and Sciences, Duke University, Durham, North Carolina 27710.
authors.forename: Volodya Y
authors.initials: VY
authors.lastname: Hayrapetyan
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: M Ilcim
authors.initials: MI
authors.lastname: Ozlu
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Karol
authors.initials: K
authors.lastname: Serafin-Molina
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: W Christopher
authors.identifier: http://orcid.org/0000-0002-2230-2865
authors.initials: WC
authors.lastname: Risher
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Tuna
authors.identifier: http://orcid.org/0000-0003-0047-0363
authors.initials: T
authors.lastname: Ustunkaya
authors.affiliation: Department of Physiology, University of Tennessee, Health Science Center, Memphis, Tennessee 38163.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dragatsis
authors.affiliation: Department of Neuroscience, University of Virginia, School of Medicine, Charlottesville, Virginia 22908, and.
authors.forename: Scott
authors.identifier: http://orcid.org/0000-0003-1054-3343
authors.initials: S
authors.lastname: Zeitlin
authors.affiliation: Department of Psychology and Neuroscience, Faculty of Arts and Sciences, Duke University, Durham, North Carolina 27710, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, Duke Institute for Brain Sciences, Durham, North Carolina 27710.
authors.forename: Henry H
authors.initials: HH
authors.lastname: Yin
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, Duke Institute for Brain Sciences, Durham, North Carolina 27710 cagla.eroglu@dm.duke.edu.
authors.forename: Cagla
authors.initials: C
authors.lastname: Eroglu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D000071058:Huntingtin Protein; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins
keywords: corticostriatal connections; excitatory synapses; huntingtin; reactive gliosis; synapse maturation; synaptogenesis