Efficient clearance of dopamine (DA) molecules from the synapse is key to regulating dopaminergic signaling. This role is fulfilled by dopamine transporters (DATs). Recent advances in structural characterization of DAT from Drosophila (dDAT) on the one hand, and imaging of dopamine neurons and the distribution and trafficking of DATs therein, on the other, now permit us for the first time to gain a mechanistic understanding of DA reuptake events in silico. Using electron microscopy images and immunofluorescence labeling of transgenic knock-in mice brain that expresses hemagglutinin epitope-tagged DAT in DA neurons, we reconstructed a realistic simulation environment for MCell simulations of DA reuptake, wherein the identity, population and kinetics of homology-modeled human DAT (hDAT) sub-states were derived from molecular simulations. The spatial distribution of DATs as well as structural heterogeneities of axon terminals near active zones were observed to give rise to large fluctuations in the density of DA in the extracelular region. The probability of attaining local DA concentrations sufficiently high to activate high affinity, and even low affinity, DA receptors, exhibited a strong dependency on the pattern of DA release: phasic release resulted in a significantly higher probability of receptor activation, compared to tonic release, even though the same average DA release frequencies were maintained during the two sets of experiments. The study highlights the significance of the irregular geometry of extrasynaptic regions, the spatial heterogeneity of DAT levels and the rates of interconversion of DAT between outward- and inward-facing states, in modulating neurotransmission.

Significance of neuronal structural complexity and spatial heterogeneity in modulating dopamine reuptake dynamics

253rd National Meeting (2017)

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