title: Striatal synaptic dysfunction and hippocampal plasticity deficits in the Hu97/18 mouse model of Huntington disease.
abstract: Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the gene (HTT) encoding the huntingtin protein (HTT). This mutation leads to multiple cellular and synaptic alterations that are mimicked in many current HD animal models. However, the most commonly used, well-characterized HD models do not accurately reproduce the genetics of human disease. Recently, a new 'humanized' mouse model, termed Hu97/18, has been developed that genetically recapitulates human HD, including two human HTT alleles, no mouse Hdh alleles and heterozygosity of the HD mutation. Previously, behavioral and neuropathological testing in Hu97/18 mice revealed many features of HD, yet no electrophysiological measures were employed to investigate possible synaptic alterations. Here, we describe electrophysiological changes in the striatum and hippocampus of the Hu97/18 mice. At 9 months of age, a stage when cognitive deficits are fully developed and motor dysfunction is also evident, Hu97/18 striatal spiny projection neurons (SPNs) exhibited small changes in membrane properties and lower amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs); however, release probability from presynaptic terminals was unaltered. Strikingly, these mice also exhibited a profound deficiency in long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, at 6 months of age we found only subtle alterations in SPN synaptic transmission, while 3-month old animals did not display any electrophysiologically detectable changes in the striatum and CA1 LTP was intact. Together, these data reveal robust, progressive deficits in synaptic function and plasticity in Hu97/18 mice, consistent with previously reported behavioral abnormalities, and suggest an optimal age (9 months) for future electrophysiological assessment in preclinical studies of HD.
authors.affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kolodziejczyk
authors.affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Parsons
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Southwell
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D006816:Huntington Disease / Q000473:pathology* / Q000503:physiopathology*; D017774:Long-Term Potentiation; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000378:metabolism; D017072:Neostriatum / Q000473:pathology* / Q000503:physiopathology*; D009473:Neuronal Plasticity; D009474:Neurons / Q000473:pathology; D017966:Pyramidal Cells / Q000473:pathology; D013569:Synapses / Q000473:pathology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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