Multi-Scale Spatial Simulations Reveal the Effect of Dopamine Transporter Localization on Dopamine Neurotransmission

Abstract

The neurotransmitter dopamine (DA) is involved in various signaling processes in the central nervous system (CNS) such as motivation, motor, reward valuation and endocrinal regulation. The expression levels of dopamine transporters (DAT), which function to clear extracellular (EC) DA, are high in dopaminergic neurons. Dopaminergic signaling relies on the localization and distribution of transporters and receptors not only at the synapses, but also at the extrasynaptic regions. Furthermore, the localization of DATs in synaptic areas, their conformational dynamics and intermolecular interactions during reuptake and release of DA, and DAT endocytosis are key processes that regulate dopaminergic signaling. Information on the spatiotemporal properties on DA release and reuptake mechanisms is limited due to limitations in current imaging techniques and difficulty of dealing with multi-scales in these models. However, fluorescence and electron microscopy provides significant information about the localization of the DATs and axonal varicosities where the DA release event occurs. This information could be transferred into a 3D reconstruction of the dopaminergic neurons and generating a multi-scale spatial model of DA-DAT transport mechanism and trafficking provides an understanding of the dynamics of system. The spatial multi-model is simulated with a hybrid solver able to solve particle based stochastic simulations and ordinary or partial differential equations. Overall, model will provide information to connect DAT trafficking and resulting localization and concentration to DA neurotransmission.