title: Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington's disease.
abstract: Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington's disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-Cre(ERT2) mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHtt-exon1 was removed and mHtt expression was terminated (Q97(CRE)). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Aldrin E
authors.initials: AE
authors.lastname: Molero
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY 10461; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Arteaga-Bracho
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY 10461; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Maria
authors.initials: M
authors.lastname: Gulinello
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Winchester
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Nandini
authors.initials: N
authors.lastname: Pichamoorthy
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Solen
authors.initials: S
authors.lastname: Gokhan
authors.affiliation: The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Kamran
authors.identifier: 0000-0001-7905-5335
authors.initials: K
authors.lastname: Khodakhah
authors.affiliation: Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY 10461; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY 10461; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461; Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461; Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461 mark.mehler@einstein.yu.edu.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Mehler
mesh_terms: D000200:Action Potentials; D000818:Animals; D017209:Apoptosis; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053580:Muscle Strength; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009928:Organ Specificity; D045442:Rotarod Performance Test
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins
keywords: neurodegeneration; plasticity; prodromal