title: Bidirectional control of postsynaptic density-95 (PSD-95) clustering by Huntingtin.
abstract: Huntington disease is associated with early alterations in corticostriatal synaptic function that precede cell death, and it is postulated that ameliorating such changes may delay clinical onset and/or prevent neurodegeneration. Although many of these synaptic alterations are thought to be attributable to a toxic gain of function of the mutant huntingtin protein, the role that nonpathogenic huntingtin (HTT) plays in synaptic function is relatively unexplored. Here, we compare the immunocytochemical localization of a major postsynaptic scaffolding protein, PSD-95, in striatal neurons from WT mice and mice overexpressing HTT with 18 glutamine repeats (YAC18, nonpathogenic). We found that HTT overexpression resulted in a palmitoylation- and BDNF-dependent increase in PSD-95 clustering at synaptic sites in striatal spiny projection neurons (SPNs) co-cultured with cortical neurons. Surprisingly, the latter effect was mediated presynaptically, as HTT overexpression in cortical neurons alone was sufficient to increase PSD-95 clustering in the postsynaptic SPNs. In contrast, antisense oligonucleotide knockdown of HTT in WT co-cultures resulted in a significant reduction of PSD-95 clustering in SPNs. Notably, despite these bidirectional changes in PSD-95 clustering, we did not observe an alteration in basal electrophysiological measures of AMPA and NMDA receptors. Thus, unlike in previous studies in the hippocampus, enhanced or decreased PSD-95 clustering alone was insufficient to drive AMPA or NMDA receptors into or out of SPN synapses. In all, our results demonstrate that nonpathogenic HTT can indeed influence synaptic protein localization and uncover a novel role of HTT in PSD-95 distribution.
authors.affiliation: From the Department of Psychiatry and Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3 and.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Parsons
authors.forename: Rujun
authors.initials: R
authors.lastname: Kang
authors.forename: Caodu
authors.initials: C
authors.lastname: Buren
authors.forename: Alejandro
authors.initials: A
authors.lastname: Dau
authors.forename: Amber L
authors.initials: AL
authors.lastname: Southwell
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Doty
authors.forename: Shaun S
authors.initials: SS
authors.lastname: Sanders
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D055785:Gene Knockdown Techniques; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D000071058:Huntingtin Protein; D054878:Lipoylation / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D051528:Guanylate Kinases
keywords: Cell Culture; Huntington Disease; Patch Clamp Electrophysiology; Post-translational Modification; Protein Palmitoylation; Synapses