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Featured ArticleResearch Articles, Cellular/Molecular

Dopamine Transporter Localization in Medial Forebrain Bundle Axons Indicates Its Long-Range Transport Primarily by Membrane Diffusion with a Limited Contribution of Vesicular Traffic on Retromer-Positive Compartments

Tarique R. Bagalkot, Ethan R. Block, Kristen Bucchin, Judith Joyce Balcita-Pedicino, Michael Calderon, Susan R. Sesack and Alexander Sorkin
Journal of Neuroscience 13 January 2021, 41 (2) 234-250; DOI: https://doi.org/10.1523/JNEUROSCI.0744-20.2020
Tarique R. Bagalkot
1Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
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Ethan R. Block
1Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
3Chatham University, Pittsburgh, Pennsylvania 15232
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Kristen Bucchin
2Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
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Judith Joyce Balcita-Pedicino
2Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
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Michael Calderon
1Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
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Susan R. Sesack
2Department of Neuroscience, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
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Alexander Sorkin
1Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
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Abstract

Dopamine transporter (DAT) controls dopamine neurotransmission by clearing synaptically released dopamine. However, trafficking itineraries of DAT, which determine its cell-surface concentration near synapses, are poorly characterized. It is especially unknown how DAT is transported between spatially distant midbrain somatodendritic and striatal axonal compartments. To examine this “long-range” trafficking, the localization and membrane diffusion of HA-epitope tagged DAT in the medial forebrain bundle (MFB) of a knock-in mouse (both sexes) were analyzed using confocal, super-resolution and EM in intact brain and acute brain slices. HA-DAT was abundant in the plasma membrane of MFB axons, similar to the striatum, although the intracellular fraction of HA-DAT in MFB was more substantial. Intracellular HA-DAT colocalized with VPS35, a subunit of the retromer complex mediating recycling from endosomes, in a subset of axons. Late endosomes, lysosomes, and endoplasmic reticulum were abundant in the soma but minimally present in MFB axons, suggesting that biosynthesis and lysosomal degradation of DAT are confined to soma. Together, the data suggest that membrane diffusion is the main mode of long-range DAT transport through MFB, although the contribution of vesicular traffic can be significant in a population of MFB axons. Based on HA-DAT diffusion rates, plasma membrane DAT in MFB axons turns over with a halftime of ∼20 d, which explains the extremely slow turnover of DAT protein in the brain. Unexpectedly, the mean diameter of DAT-labeled MFB axons was observed to be twice larger than reported for striatum. The implications of this finding for dopamine neuron physiology are discussed.

SIGNIFICANCE STATEMENT The dopamine transporter (DAT) is a key regulator of dopamine neurotransmission and a target of abused psychostimulants. In the present study, we examined, for the first time, mechanisms of the long-range traffic of DAT in intact brain and acute brain slices from the knock-in mouse expressing epitope-tagged DAT. Using a combination of confocal, super-resolution and EM, we defined DAT localization and its membrane diffusion parameters in medial forebrain bundle axonal tracts connecting midbrain somatodendritic and striatal axonal compartments of dopaminergic neurons. In contrast to the widely accepted model of long-range axonal transport, our studies suggest that DAT traffics between midbrain and striatum, mainly by lateral diffusion in the plasma membrane with only a limited contribution of vesicular transport in recycling endosomes.

  • dopamine transporter
  • EM
  • mouse brain
  • trafficking

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The Journal of Neuroscience: 41 (2)
Journal of Neuroscience
Vol. 41, Issue 2
13 Jan 2021
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Dopamine Transporter Localization in Medial Forebrain Bundle Axons Indicates Its Long-Range Transport Primarily by Membrane Diffusion with a Limited Contribution of Vesicular Traffic on Retromer-Positive Compartments
Tarique R. Bagalkot, Ethan R. Block, Kristen Bucchin, Judith Joyce Balcita-Pedicino, Michael Calderon, Susan R. Sesack, Alexander Sorkin
Journal of Neuroscience 13 January 2021, 41 (2) 234-250; DOI: 10.1523/JNEUROSCI.0744-20.2020

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Dopamine Transporter Localization in Medial Forebrain Bundle Axons Indicates Its Long-Range Transport Primarily by Membrane Diffusion with a Limited Contribution of Vesicular Traffic on Retromer-Positive Compartments
Tarique R. Bagalkot, Ethan R. Block, Kristen Bucchin, Judith Joyce Balcita-Pedicino, Michael Calderon, Susan R. Sesack, Alexander Sorkin
Journal of Neuroscience 13 January 2021, 41 (2) 234-250; DOI: 10.1523/JNEUROSCI.0744-20.2020
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Keywords

  • dopamine transporter
  • EM
  • mouse brain
  • trafficking

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