Reduced expression of the vesicular acetylcholine transporter causes learning deficits in mice

Authors

  • B. M. De Castro,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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    • 1

      These authors contributed equally to this work.

  • ,1 G. S. Pereira,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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    • 1

      These authors contributed equally to this work.

  • ,1 V. Magalhães,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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    • 1

      These authors contributed equally to this work.

  • ,1 J. I. Rossato,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • X. De Jaeger,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • C. Martins-Silva,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • B. Leles,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • P Lima,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • M. V. Gomez,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • R. R. Gainetdinov,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • , M. G. Caron,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • I. Izquierdo,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • M. Cammarota,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • V. F. Prado,

    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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  • and ,,, M. A. M. Prado ,,,,

    Corresponding author
    1. Program in Molecular Pharmacology, ICB and Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, §Centro de Memoria, Instituto de Pesquisas Biomedicas, Pontificia Universidade Catolica de Rio Grande do Sul (PUC-RS), Brazil, Department of Cell Biology, Duke University, Durham, NC, USA, **Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genova, Italy, ††Departamento de Bioquímica-Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil, ‡‡Robarts Research Institute, §§Department of Anatomy and Cell Biology, and ¶¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
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*M. A. M. Prado, Robarts Research Institute, 100 Perth Drive, N6A 5K8, London, Ontario, Canada. E-mail: mprado@robarts.ca

Abstract

Storage of acetylcholine in synaptic vesicles plays a key role in maintaining cholinergic function. Here we used mice with a targeted mutation in the vesicular acetylcholine transporter (VAChT) gene that reduces transporter expression by 40% to investigate cognitive processing under conditions of VAChT deficiency. Motor skill learning in the rotarod revealed that VAChT mutant mice were slower to learn this task, but once they reached maximum performance they were indistinguishable from wild-type mice. Interestingly, motor skill performance maintenance after 10 days was unaffected in these mutant mice. We also tested whether reduced VAChT levels affected learning in an object recognition memory task. We found that VAChT mutant mice presented a deficit in memory encoding necessary for the temporal order version of the object recognition memory, but showed no alteration in spatial working memory, or spatial memory in general when tested in the Morris water maze test. The memory deficit in object recognition memory observed in VAChT mutant mice could be reversed by cholinesterase inhibitors, suggesting that learning deficits caused by reduced VAChT expression can be ameliorated by restoring ACh levels in the synapse. These data indicate an important role for cholinergic tone in motor learning and object recognition memory.

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