Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein

Authors

  • Hoa A. Lam,

    1. Hatos Center, University of California Los Angeles, Los Angeles, California
    2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    3. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
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  • Nanping Wu,

    1. Intellectual and Developmental Disabilities Research Center, University of California Los Angeles, Los Angeles, California
    2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    3. Brain Research Institute, University of California Los Angeles, Los Angeles, California
    4. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
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  • Ingrid Cely,

    1. Hatos Center, University of California Los Angeles, Los Angeles, California
    2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    3. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
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  • Rachel L. Kelly,

    1. Hatos Center, University of California Los Angeles, Los Angeles, California
    2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    3. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
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  • Sindalana Hean,

    1. Department of Neurology, University of California Los Angeles, Los Angeles, California
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  • Franziska Richter,

    1. Department of Neurology, University of California Los Angeles, Los Angeles, California
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  • Iddo Magen,

    1. Department of Neurology, University of California Los Angeles, Los Angeles, California
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  • Carlos Cepeda,

    1. Intellectual and Developmental Disabilities Research Center, University of California Los Angeles, Los Angeles, California
    2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    3. Brain Research Institute, University of California Los Angeles, Los Angeles, California
    4. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
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  • Larry C. Ackerson,

    1. Hatos Center, University of California Los Angeles, Los Angeles, California
    2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    3. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
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  • Wendy Walwyn,

    1. Hatos Center, University of California Los Angeles, Los Angeles, California
    2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    3. Brain Research Institute, University of California Los Angeles, Los Angeles, California
    4. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
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  • Eliezer Masliah,

    1. Department of Neuroscience, University of California San Diego, La Jolla, California
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  • Marie-Françoise Chesselet,

    1. Brain Research Institute, University of California Los Angeles, Los Angeles, California
    2. Department of Neurology, University of California Los Angeles, Los Angeles, California
    3. Department of Neurobiology, University of California Los Angeles, Los Angeles, California
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  • Michael S. Levine,

    1. Intellectual and Developmental Disabilities Research Center, University of California Los Angeles, Los Angeles, California
    2. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    3. Brain Research Institute, University of California Los Angeles, Los Angeles, California
    4. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
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  • Nigel T. Maidment

    Corresponding author
    1. Hatos Center, University of California Los Angeles, Los Angeles, California
    2. Intellectual and Developmental Disabilities Research Center, University of California Los Angeles, Los Angeles, California
    3. Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California
    4. Brain Research Institute, University of California Los Angeles, Los Angeles, California
    5. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California
    • Department of Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024
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Abstract

Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson's disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson's disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine. © 2011 Wiley-Liss, Inc.

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