title: Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.
abstract: Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.
authors.affiliation: School of Physiology & Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: J
authors.initials: J
authors.lastname: Witton
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: R
authors.initials: R
authors.lastname: Padmashri
authors.affiliation: School of Physiology & Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: L E
authors.initials: LE
authors.lastname: Zinyuk
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Reg. 142290, Russia.|The Open University, Department of Life Sciences, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: V I
authors.initials: VI
authors.lastname: Popov
authors.affiliation: The Open University, Department of Life Sciences, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: I
authors.initials: I
authors.lastname: Kraev
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Line
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: T P
authors.initials: TP
authors.lastname: Jensen
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Tedoldi
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Cummings
authors.affiliation: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: V L J
authors.initials: VLJ
authors.lastname: Tybulewicz
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: E M C
authors.initials: EMC
authors.lastname: Fisher
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: School of Physiology & Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Randall
authors.affiliation: School of Physiology & Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: Brown
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: F A
authors.initials: FA
authors.lastname: Edwards
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.|Laboratory of Brain Microcircuits, Institute of Biology and Biomedicine, University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia.
authors.forename: D A
authors.initials: DA
authors.lastname: Rusakov
authors.affiliation: The Open University, Department of Life Sciences, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: M G
authors.initials: MG
authors.lastname: Stewart
authors.affiliation: School of Physiology & Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: M W
authors.initials: MW
authors.lastname: Jones
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D018891:Dentate Gyrus / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000473:pathology / Q000503:physiopathology*; D009924:Organ Culture Techniques; D014314:Trisomy / Q000235:genetics