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Nat Neurosci. 2015 Sep;18(9):1291-1298. doi: 10.1038/nn.4072. Epub 2015 Aug 3.

Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.

Author information

1
School of Physiology & Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK.
2
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
3
Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Reg. 142290, Russia.
4
The Open University, Department of Life Sciences, Walton Hall, Milton Keynes, MK7 6AA, UK.
5
Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK.
6
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
7
MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
8
Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
9
Laboratory of Brain Microcircuits, Institute of Biology and Biomedicine, University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia.
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Contributed equally

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.

PMID:
26237367
PMCID:
PMC4552261
DOI:
10.1038/nn.4072
[Indexed for MEDLINE]
Free PMC Article

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