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Spatial and temporal scales of dopamine transmission

Abstract

Dopamine is a prototypical neuromodulator that controls circuit function through G protein-coupled receptor signalling. Neuromodulators are volume transmitters, with release followed by diffusion for widespread receptor activation on many target cells. Yet, we are only beginning to understand the specific organization of dopamine transmission in space and time. Although some roles of dopamine are mediated by slow and diffuse signalling, recent studies suggest that certain dopamine functions necessitate spatiotemporal precision. Here, we review the literature describing dopamine signalling in the striatum, including its release mechanisms and receptor organization. We then propose the domain-overlap model, in which release and receptors are arranged relative to one another in micrometre-scale structures. This architecture is different from both point-to-point synaptic transmission and the widespread organization that is often proposed for neuromodulation. It enables the activation of receptor subsets that are within micrometre-scale domains of release sites during baseline activity and broader receptor activation with domain overlap when firing is synchronized across dopamine neuron populations. This signalling structure, together with the properties of dopamine release, may explain how switches in firing modes support broad and dynamic roles for dopamine and may lead to distinct pathway modulation.

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Fig. 1: Modes of chemical transmission.
Fig. 2: Measurements of dopamine transmission.
Fig. 3: Sparse dopamine release sites.
Fig. 4: Dopamine neuron firing and release.
Fig. 5: Dopamine receptor organization and activation.
Fig. 6: The domain-overlap model.

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Acknowledgements

Work on dopamine and synaptic transmission in the Kaeser laboratory is supported by the US National Institutes of Health (R01NS103484, R01NS083898, R01MH113349 to P.S.K.), the Dean’s Initiative Award for Innovation (to P.S.K.), the Lefler Foundation (to P.S.K.), a Gordon postdoctoral fellowship (to C.L.), and a Damon Runyon postdoctoral fellowship (DRG-2417-20 to P.G.). The authors thank J. Williams and R. Wise for comments and discussions. The authors apologize to colleagues whose work they could not cite as not all important work could be included owing to space restrictions.

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Correspondence to Pascal S. Kaeser.

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Glossary

Varicosities

Enlarged compartments of dopamine axons filled with small, clear vesicles; varicosities are similar to presynaptic boutons but are often not associated with well-defined postsynaptic specializations.

Quantal release events

Events involving fusion of a single vesicle, leading to the release of neurotransmitters from that vesicle.

Symmetric synapses

Synapses in which the presynaptic and postsynaptic electron densities appear similar, contrasting asymmetric synapses in which the postsynaptic densities are more prominent.

Chromaffin cells

Endocrine cells in the adrenal medulla that secrete catecholamines; chromaffin cells are a widely used model to study exocytosis.

Readily releasable pool

(RRP). The subset of vesicles within a nerve terminal that can be quickly released by an action potential; readily releasable vesicles are often docked.

Vesicular release probability

(P). The probability with which a vesicle from the readily releasable pool fuses with the presynaptic plasma membrane in response to an action potential.

Depression

A decrease in release during or following repetitive firing; depression is typically a result of deletion of the readily releasable pool owing to a high P.

Somatodendritic release

Release from neuronal somata and dendrites (as opposed to axons); somatodendritic dopamine release is mediated by exocytosis and is an important feature of dopamine neurons.

Pacemaker currents

Cell-autonomous, spontaneous currents that drive the tonic firing of dopamine neurons; they are mainly mediated by Ca2+ channels.

Refractory sites

Sites at which a vesicle has fused become refractory and are unavailable for immediate reuse because the readily releasable pool is depleted and because material from the preceding fusion event needs to be cleared.

Direct and indirect pathways

The prominent output circuits of the striatum that originate from separate medium spiny neuron populations and project to distinct target areas.

Dissociation constant

An equilibrium constant that specifies the tendency of an agent to separate from its target; a high dissociation constant reflects a low binding affinity.

Dwell times

The period of time for which a ligand is bound to its target; prolonged dopamine dwell times generally result in enhanced dopamine receptor signalling.

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Liu, C., Goel, P. & Kaeser, P.S. Spatial and temporal scales of dopamine transmission. Nat Rev Neurosci 22, 345–358 (2021). https://doi.org/10.1038/s41583-021-00455-7

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