Calbindin-D28K Limits Dopamine Release in Ventral but Not Dorsal Striatum by Regulating Ca 2+ Availability and Dopamine Transporter Function

The calcium-binding protein calbindin-D28K, or calb1, is expressed at higher levels by dopamine (DA) neurons originating in the ventral tegmental area (VTA) than in the adjacent substantia nigra pars compacta (SNc). Calb1 has received attention for a potential role in neuroprotection in Parkinson�...

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Published in:ACS chemical neuroscience 2019-08, Vol.10 (8), p.3419-3426
Main Authors: Brimblecombe, Katherine R, Vietti-Michelina, Stefania, Platt, Nicola J, Kastli, Rahel, Hnieno, Ahmad, Gracie, Caitlin J, Cragg, Stephanie J
Format: Article
Language:English
Subjects:
Animals
Calbindin 1 - metabolism
Calcium - metabolism
Corpus Striatum - metabolism
Dopamine - metabolism
Dopamine Plasma Membrane Transport Proteins - metabolism
Dopaminergic Neurons - metabolism
Gene Knockdown Techniques
Mice
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Summary:The calcium-binding protein calbindin-D28K, or calb1, is expressed at higher levels by dopamine (DA) neurons originating in the ventral tegmental area (VTA) than in the adjacent substantia nigra pars compacta (SNc). Calb1 has received attention for a potential role in neuroprotection in Parkinson's disease. The underlying physiological roles for calb1 are incompletely understood. We used cre-loxP technology to knock down calb1 in mouse DA neurons to test whether calb1 governs axonal release of DA in the striatum, detected using fast-scan cyclic voltammetry ex vivo. In the ventral but not dorsal striatum, calb1 knockdown elevated DA release and modified the spatiotemporal coupling of Ca entry to DA release. Furthermore, calb1 knockdown enhanced DA uptake but attenuated the impact of DA transporter (DAT) inhibition by cocaine on underlying DA release. These data reveal that calb1 acts through a range of mechanisms underpinning both DA release and uptake to limit DA transmission in the ventral but not dorsal striatum.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.9b00325