Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome

Jonathan Witton; Ragunathan Padmashri; Larissa E. Zinyuk; Victor I. Popov; Igor Kraev; Samantha J. Line; Thomas P. Jensen; Angelo Tedoldi; Damian M. Cummings; Victor L.J. Tybulewicz; Elizabeth M.C. Fisher; David M. Bannerman; Andrew D. Randall; Jonathan T. Brown; Frances A. Edwards; Dmitri A. Rusakov; Michael G. Stewart; Matt W. Jones

doi:10.1038/nn.4072

Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome

Jonathan Witton, Ragunathan Padmashri, Larissa E. Zinyuk, Victor I. Popov, Igor Kraev, Samantha J. Line, Thomas P. Jensen, Angelo Tedoldi, Damian M. Cummings, Victor L.J. Tybulewicz, Elizabeth M.C. Fisher, David M. Bannerman, Andrew D. Randall, Jonathan T. Brown, Frances A. Edwards, Dmitri A. Rusakov, Michael G. Stewart, Matt W. Jones

Neurological Sciences

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31 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1291-1298
Number of pages	8
Journal	Nature Neuroscience
Volume	18
Issue number	9
DOIs	https://doi.org/10.1038/nn.4072
State	Published - Aug 26 2015

ASJC Scopus subject areas

General Neuroscience

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Witton, J., Padmashri, R., Zinyuk, L. E., Popov, V. I., Kraev, I., Line, S. J., Jensen, T. P., Tedoldi, A., Cummings, D. M., Tybulewicz, V. L. J., Fisher, E. M. C., Bannerman, D. M., Randall, A. D., Brown, J. T., Edwards, F. A., Rusakov, D. A., Stewart, M. G., & Jones, M. W. (2015). Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome. Nature Neuroscience, 18(9), 1291-1298. https://doi.org/10.1038/nn.4072

Witton, J, Padmashri, R, Zinyuk, LE, Popov, VI, Kraev, I, Line, SJ, Jensen, TP, Tedoldi, A, Cummings, DM, Tybulewicz, VLJ, Fisher, EMC, Bannerman, DM, Randall, AD, Brown, JT, Edwards, FA, Rusakov, DA, Stewart, MG & Jones, MW 2015, 'Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome', Nature Neuroscience, vol. 18, no. 9, pp. 1291-1298. https://doi.org/10.1038/nn.4072

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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.",

author = "Jonathan Witton and Ragunathan Padmashri and Zinyuk, {Larissa E.} and Popov, {Victor I.} and Igor Kraev and Line, {Samantha J.} and Jensen, {Thomas P.} and Angelo Tedoldi and Cummings, {Damian M.} and Tybulewicz, {Victor L.J.} and Fisher, {Elizabeth M.C.} and Bannerman, {David M.} and Randall, {Andrew D.} and Brown, {Jonathan T.} and Edwards, {Frances A.} and Rusakov, {Dmitri A.} and Stewart, {Michael G.} and Jones, {Matt W.}",

note = "Funding Information: Thanks to A. Slender, H. Davies and D. Ford for expert technical assistance and to the Wellcome Trust (Programme Grant to E.M.C.F., V.L.J.T. and M.W.J., Principal Fellowship to D.A.R.), the UK Medical Research Council (grant to E.M.C.F. and V.L.J.T., Industrial Collaborative Studentship to J.W.), Biotechnology and Biological Sciences Research Council (grant to M.G.S.), European Research Council Advanced Grant and FP7 ITN Extrabrain (to D.A.R.) Russian Science Foundation grant 15-14-30000 (to D.A.R.) and Russian Foundation for Basic Research grant 08-04-00049a (to V.I.P.) for financial support.",

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AU - Padmashri, Ragunathan

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AU - Kraev, Igor

AU - Line, Samantha J.

AU - Jensen, Thomas P.

AU - Tedoldi, Angelo

AU - Cummings, Damian M.

AU - Tybulewicz, Victor L.J.

AU - Fisher, Elizabeth M.C.

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AU - Randall, Andrew D.

AU - Brown, Jonathan T.

AU - Edwards, Frances A.

AU - Rusakov, Dmitri A.

AU - Stewart, Michael G.

AU - Jones, Matt W.

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AB - 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.

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Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome

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