Disruption of the PDZ domain-binding motif of the dopamine transporter uniquely alters nanoscale distribution, dopamine homeostasis, and reward motivation.

Autor:	Sørensen G; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Mental Health Center & University of Copenhagen, Copenhagen, Denmark., Rickhag M; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Leo D; Neuroscience and Brain Technologies Department, Italian Institute of Technology, Genoa, Italy., Lycas MD; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Ridderstrøm PH; Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Mental Health Center & University of Copenhagen, Copenhagen, Denmark., Weikop P; Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Mental Health Center & University of Copenhagen, Copenhagen, Denmark., Lilja JH; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Rifes P; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Herborg F; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Woldbye D; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Wörtwein G; Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Mental Health Center & University of Copenhagen, Copenhagen, Denmark., Gainetdinov RR; Institute of Translational Biomedicine and Saint-Petersburg University Hospital, Saint-Petersburg State University, Saint-Petersburg, Russia., Fink-Jensen A; Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen, Mental Health Center & University of Copenhagen, Copenhagen, Denmark., Gether U; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: gether@sund.ku.dk.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Dec; Vol. 297 (6), pp. 101361. Date of Electronic Publication: 2021 Oct 29.
DOI:	10.1016/j.jbc.2021.101361
Abstrakt:	The dopamine (DA) transporter (DAT) is part of a presynaptic multiprotein network involving interactions with scaffold proteins via its C-terminal PDZ domain-binding sequence. Using a mouse model expressing DAT with mutated PDZ-binding sequence (DAT-AAA), we previously demonstrated the importance of this binding sequence for striatal expression of DAT. Here, we show by application of direct stochastic reconstruction microscopy not only that the striatal level of transporter is reduced in DAT-AAA mice but also that the nanoscale distribution of this transporter is altered with a higher propensity of DAT-AAA to localize to irregular nanodomains in dopaminergic terminals. In parallel, we observe mesostriatal DA adaptations and changes in DA-related behaviors distinct from those seen in other genetic DAT mouse models. DA levels in the striatum are reduced to ∼45% of that of WT, accompanied by elevated DA turnover. Nonetheless, fast-scan cyclic voltammetry recordings on striatal slices reveal a larger amplitude and prolonged clearance rate of evoked DA release in DAT-AAA mice compared with WT mice. Autoradiography and radioligand binding show reduced DA D2 receptor levels, whereas immunohistochemistry and autoradiography show unchanged DA D1 receptor levels. In behavioral experiments, we observe enhanced self-administration of liquid food under both a fixed ratio of one and progressive ratio schedule of reinforcement but a reduction compared with WT when using cocaine as reinforcer. In summary, our data demonstrate how disruption of PDZ domain interactions causes changes in DAT expression and its nanoscopic distribution that in turn alter DA clearance dynamics and related behaviors. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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