Dopaminergic neurons establish a distinctive axonal arbor with a majority of non-synaptic terminals

FASEB J. 2021 Aug;35(8):e21791. doi: 10.1096/fj.202100201RR.


Chemical neurotransmission typically occurs through synapses. Previous ultrastructural examinations of monoamine neuron axon terminals often failed to identify a pre- and postsynaptic coupling, leading to the concept of "volume" transmission. Whether this results from intrinsic properties of these neurons remains undefined. We find that dopaminergic neurons in vitro establish a distinctive axonal arbor compared to glutamatergic or GABAergic neurons in both size and propensity of terminals to avoid direct contact with target neurons. While most dopaminergic varicosities are active and contain exocytosis proteins like synaptotagmin 1, only ~20% of these are synaptic. The active zone protein bassoon was found to be enriched in dopaminergic terminals that are in proximity to a target cell. Finally, we found that the proteins neurexin-1αSS4- and neuroligin-1A+B play a critical role in the formation of synapses by dopamine (DA) neurons. Our findings suggest that DA neurons are endowed with a distinctive developmental connectivity program.

Keywords: active zone; axon terminals; dopamine; exocytosis; synapse; volume transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / physiology*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cell Differentiation
  • Coculture Techniques / methods
  • Corpus Striatum / cytology*
  • Dopamine / genetics
  • Dopamine / metabolism*
  • Dopaminergic Neurons / physiology*
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Immunohistochemistry
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Cell Adhesion Molecules / genetics
  • Neural Cell Adhesion Molecules / metabolism*
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / metabolism


  • Bsn protein, mouse
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • neuroligin 1
  • Green Fluorescent Proteins
  • Tyrosine 3-Monooxygenase
  • Dopamine

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