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Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers

A figure from this studyHot Off the Press – August 15, 2022

Summary

Communication between brain cells (neurons) generally involves the unidirectional flow of information. Input from upstream cells arrives onto the dendrites, gets processed in the cell body where it is converted into a rapid electrical wave (action potential) that travels down the axon to trigger the release of neurotransmitter molecules from axon terminals onto the dendrites of downstream cells. The signal is passed from one cell to the next at the synapse, which is a structure where the axon of one cell and dendrite of another nearly touch. However, dopamine-releasing neurons seem to take a shortcut: the axons of dopaminergic neurons receive input directly from upstream acetylcholine-releasing neurons that may influence the neurotransmitter release of dopaminergic terminals. Until now, how this communication occurs between cells that bypasses dendrites was a mystery. In a recent trans-NIH collaborative study led by Dr. Zayd Khaliq (NINDS, jointly appointed at NIDA), the research team made technically challenging recordings of electrical signals from the midbrain dopaminergic axons. Although dopaminergic axons lack classic synapses, signaling onto axons of dopaminergic neurons occurs very much like what happens in a traditional dendritic synapse, including the ability to initiate spontaneous axonal action potentials. This observation goes against the classical notion of unidirectional flow of information in the nervous system. This phenomenon was observed in rodents and also in Rhesus macaque brains and provides a new framework for understanding the flow of information in the brain pointing to possible new targets for treating substance use disorders and Parkinson’s Disease.

Publication Information

Kramer, Paul F; Brill-Weil, Samuel G; Cummins, Alex C; Zhang, Renshu; Camacho-Hernandez, Gisela A; Newman, Amy Hauck; Eldridge, Mark A G; Averbeck, Bruno B; Khaliq, Zayd M

Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers Journal Article

In: Neuron, 2022, ISSN: 1097-4199.

Abstract | Links

@article{pmid35931070,
title = {Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers},
author = {Paul F Kramer and Samuel G Brill-Weil and Alex C Cummins and Renshu Zhang and Gisela A Camacho-Hernandez and Amy Hauck Newman and Mark A G Eldridge and Bruno B Averbeck and Zayd M Khaliq},
url = {https://pubmed.ncbi.nlm.nih.gov/35931070/},
doi = {10.1016/j.neuron.2022.07.011},
issn = {1097-4199},
year = {2022},
date = {2022-08-01},
urldate = {2022-08-01},
journal = {Neuron},
abstract = {Transmission from striatal cholinergic interneurons (CINs) controls dopamine release through nicotinic acetylcholine receptors (nAChRs) on dopaminergic axons. Anatomical studies suggest that cholinergic terminals signal predominantly through non-synaptic volume transmission. However, the influence of cholinergic transmission on electrical signaling in axons remains unclear. We examined axo-axonal transmission from CINs onto dopaminergic axons using perforated-patch recordings, which revealed rapid spontaneous EPSPs with properties characteristic of fast synapses. Pharmacology showed that axonal EPSPs (axEPSPs) were mediated primarily by high-affinity α6-containing receptors. Remarkably, axEPSPs triggered spontaneous action potentials, suggesting that these axons perform integration to convert synaptic input into spiking, a function associated with somatodendritic compartments. We investigated the cross-species validity of cholinergic axo-axonal transmission by recording dopaminergic axons in macaque putamen and found similar axEPSPs. Thus, we reveal that synaptic-like neurotransmission underlies cholinergic signaling onto dopaminergic axons, supporting the idea that striatal dopamine release can occur independently of somatic firing to provide distinct signaling.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

Transmission from striatal cholinergic interneurons (CINs) controls dopamine release through nicotinic acetylcholine receptors (nAChRs) on dopaminergic axons. Anatomical studies suggest that cholinergic terminals signal predominantly through non-synaptic volume transmission. However, the influence of cholinergic transmission on electrical signaling in axons remains unclear. We examined axo-axonal transmission from CINs onto dopaminergic axons using perforated-patch recordings, which revealed rapid spontaneous EPSPs with properties characteristic of fast synapses. Pharmacology showed that axonal EPSPs (axEPSPs) were mediated primarily by high-affinity α6-containing receptors. Remarkably, axEPSPs triggered spontaneous action potentials, suggesting that these axons perform integration to convert synaptic input into spiking, a function associated with somatodendritic compartments. We investigated the cross-species validity of cholinergic axo-axonal transmission by recording dopaminergic axons in macaque putamen and found similar axEPSPs. Thus, we reveal that synaptic-like neurotransmission underlies cholinergic signaling onto dopaminergic axons, supporting the idea that striatal dopamine release can occur independently of somatic firing to provide distinct signaling.

Close

  • https://pubmed.ncbi.nlm.nih.gov/35931070/
  • doi:10.1016/j.neuron.2022.07.011

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