title: Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington's disease.
abstract: Huntington's disease (HD) is an autosomal dominant disease that develops in midlife (~ 40 years-old at onset) and then progresses slowly. It is still unclear how striatal medium spiny neurons (MSNs), the most vulnerable neurons in HD, maintain their function for decades despite the chronic expression of mutant huntingtin (mHTT). In this study, we used aged BACHD mice, a HD model expressing the full-length human mHTT gene, to investigate the molecular, morphological and functional properties of striatal MSNs. We report that the density of dendritic spines in MSNs is substantially lower in aged BACHD mice than in wild-type (WT) mice, in the absence of major dendritic changes and neuronal loss. This spine loss is accompanied by changes in transcription, resulting in a low expression of the striatum-specific G protein-coupled receptor 88 (Gpr88) as well as a reorganization of the composition of AMPAR subunits (high Gria1/Gria2 mRNA ratio). We also detected functional changes in BACHD MSNs. Notably, BACHD MSNs were hyperexcitable and the amplitude of AMPAR-mediated synaptic currents was higher than in WT MSNs. Altogether, these data show that both the intrinsic properties and the strength of the remaining synapses are modified in MSNs with low dendritic spine density in aged BACHD mice. These homeostatic mechanisms may compensate for the substantial loss of synaptic inputs and thus alleviate the deleterious effects of mHTT expression on the activity of MSNs and also possibly on the motor phenotype in aged BACHD.
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France. Electronic address: anne-berengere.rocher@unil.ch.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Rocher
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR7288, 13009 Marseille, France.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gubellini
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Merienne
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Boussicault
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Petit
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gipchtein
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jan
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, F-92260 Fontenay-aux-Roses, France. Electronic address: gilles.bonvento@cea.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Bonvento
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology*
chemical_list: C485998:Gpr88 protein, mouse; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D018091:Receptors, AMPA; D043562:Receptors, G-Protein-Coupled
keywords: AMPAR; Dendritic spine; Homeostatic scaling; Huntington's disease; Medium spiny neuron; Whole-cell patch-clamp