Calbindin-D28K Limits Dopamine Release in Ventral but Not Dorsal Striatum by Regulating Ca2+ Availability and Dopamine Transporter Function

Katherine R Brimblecombe,Ahmad Hnieno,Caitlin J Gracie,Stefania Vietti-Michelina,Nicola J Platt,Stephanie J Cragg,Rahel Kastli

doi:10.1021/acschemneuro.9b00325

Katherine R Brimblecombe, Ahmad Hnieno + Show 5 more

Open Access

https://doi.org/10.1021/acschemneuro.9b00325

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Journal: ACS chemical neuroscience	Publication Date: Jul 30, 2019
Citations: 19	License type: cc-by

Affiliation: University of Oxford

Abstract

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 Ca2+ 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.

Highlights

The substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) comprise a contiguous but molecularly heterogeneous collection of dopaminergic neurons that innervate the striatum in a topographic pattern, innervating predominantly the dorsal and ventral striatum, respectively.[1,2]
We utilized a cre-loxP approach to knock down calb[1] from DA neurons selectively to address whether calb[1] regulates axonal DA release in dorsal or ventral striatum, and whether it impacts on different Ca2+-dependence and spatiotemporal coupling
ACS Chemical Neuroscience compared to true wild-type mice[22] and slightly prolonged time courses for uptake for DA transients, there is no net change in peak extracellular concentration of DA ([DA]o) detected in our data set (Figure S2)

Summary

Introduction

The substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) comprise a contiguous but molecularly heterogeneous collection of dopaminergic neurons that innervate the striatum in a topographic pattern, innervating predominantly the dorsal and ventral striatum, respectively.[1,2] These DA neurons show heterogeneity in their expression levels of mRNA or protein for a diverse range of molecules that include D2 receptors, DA transporter (DAT), and calcium-binding protein calbindin-D28k (calb1).[1,3−7] Calb[1] is expressed in VTA DA neurons at ∼2−3-fold higher levels than in SNc3,5,7,8 and is a fast, high affinity, and mobile buffer.[9−11] The function of calb[1] in DA neurons has not been well-defined, but calb[1] has been of long-standing interest as a marker of preserved DA neurons in Parkinson’s disease.[12,13]. In CPu, consistent with the lack of effect of calb[1] knockdown on evoked [DA]o, there was no difference in the relationship between [Ca2+]o (range 0.6−4.8 mM) and evoked [DA]o in CalbKD vs CalbWT mice

Results

Conclusion