Human Molecular Genetics Advance Access originally published online on January 29, 2009
Human Molecular Genetics 2009 18(8):1449-1463; doi:10.1093/hmg/ddp055
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Impairments in motor coordination without major changes in cerebellar plasticity in the Tc1 mouse model of Down syndrome
,*1 Laboratoire de Pharmacologie de la Synapse, CNRS UMR 8619, Université Paris-Sud, 91405 Orsay Cedex, France 2 Division of Neurophysiology 3 Division of Immune Cell Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK 4 Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
* To whom correspondence should be addressed at: Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication (NAMC), CNRS UMR 8620, Université Paris-Sud, 91405 Orsay Cedex, France. Tel: +33 169154996; Fax: +33 169157726; Email: elise.morice{at}u-psud.fr
Received December 9, 2008; Revised January 27, 2009; Accepted January 27, 2009
Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of human chromosome 21 (Hsa21). Recently, O'Doherty et al. [An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 309 (2005) 2033–2037] generated a trans-species aneuploid mouse line (Tc1) that carries an almost complete Hsa21. The Tc1 mouse is the most complete animal model for DS currently available. Tc1 mice show many features that relate to human DS, including alterations in memory, synaptic plasticity, cerebellar neuronal number, heart development and mandible size. Because motor deficits are one of the most frequently occurring features of DS, we have undertaken a detailed analysis of motor behaviour in cerebellum-dependent learning tasks that require high motor coordination and balance. In addition, basic electrophysiological properties of cerebellar circuitry and synaptic plasticity have been investigated. Our results reveal that, compared with controls, Tc1 mice exhibit a higher spontaneous locomotor activity, a reduced ability to habituate to their environments, a different gait and major deficits on several measures of motor coordination and balance in the rota rod and static rod tests. Moreover, cerebellar long-term depression is essentially normal in Tc1 mice, with only a slight difference in time course. Our observations provide further evidence that support the validity of the Tc1 mouse as a model for DS, which will help us to provide insights into the causal factors responsible for motor deficits observed in persons with DS.
Present address: Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication (NAMC), CNRS UMR 8620, Université Paris-Sud, 91405 Orsay Cedex, France.
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