Increased striatal dopamine release and hyperdopaminergic-like behaviour in mice lacking both alpha-synuclein and gamma-synuclein

Authors

  • Steven L. Senior,

    1. Wellcome Trust Centre For Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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    • *

      Present address: Department of Physiology, Anatomy & Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford OX1 3QX, UK.

  • Natalia Ninkina,

    1. School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK
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  • Robert Deacon,

    1. Department of Experimental Psychology, University of Oxford, Parks Road, Oxford OX1 3UD, UK
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  • David Bannerman,

    1. Department of Experimental Psychology, University of Oxford, Parks Road, Oxford OX1 3UD, UK
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  • Vladimir L. Buchman,

    1. School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK
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  • Stephanie J. Cragg,

    1. Department of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, South Parks Road, Oxford OX1 3PT, UK
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  • Richard Wade-Martins

    1. Wellcome Trust Centre For Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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    • *

      Present address: Department of Physiology, Anatomy & Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford OX1 3QX, UK.


Dr R. Wade-Martins, at *present address below.
E-mail: richard.wade-martins@well.ox.ac.uk or richard.wade-martins@dpag.ox.ac.uk

Abstract

Alpha-synuclein is intimately involved in the pathogenesis of Parkinson's disease, and has been implicated in the regulation of synthesis, release and reuptake of dopamine (DA). However, mice lacking members of the synuclein family have been reported to display no overt behavioural phenotype. This may be a result of compensatory upregulation of other synucleins during development. Here we report on behaviour and DA synapse function of alpha-synuclein null, gamma-synuclein null, and alpha-gamma-synuclein double-null knockout mice. Double-null mice were hyperactive in a novel environment and alternated at a lower rate in a T-maze spontaneous alternation task, a phenotype reminiscent of mice expressing reduced levels of the DA transporter. To investigate a possible hyperdopaminergic phenotype in alpha-gamma-synuclein double-null mice, we used fast-scan cyclic voltammetry at carbon-fibre microelectrodes to assess DA release and reuptake in striatal slices from wild-type, alpha-null, gamma-null and double-null mice in real time. Double-null mice were found to have a twofold increase in the extracellular concentration of DA detected after discrete electrical stimuli in the striatum. By measuring the rate of reuptake of DA and tissue DA content in these animals, we showed that the observed increase in size of striatal DA transients was not attributable to a decrease in reuptake of DA via the DA transporter, and can not be attributed to an increase in tissue DA levels in the striatum. Rather, we propose that loss of both alpha- and gamma-synuclein causes an increase in release probability from dopaminergic synapses.

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