Corelease of acetylcholine and GABA from cholinergic forebrain neurons

  1. Arpiar Saunders
  2. Adam J Granger
  3. Bernardo L Sabatini  Is a corresponding author
  1. Howard Hughes Medical Institute, Harvard Medical School, United States

Abstract

Neurotransmitter corelease is emerging as a common theme of central neuromodulatory systems. Though corelease of glutamate or GABA with acetylcholine has been reported within the cholinergic system, the full extent is unknown. To explore synaptic signaling of cholinergic forebrain neurons, we activated choline acetyltransferase expressing neurons using channelrhodopsin while recording post-synaptic currents (PSCs) in layer 1 interneurons. Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors. Based on PSC latency and pharmacological sensitivity, our results suggest monosynaptic release of both GABA and ACh. Anatomical analysis showed that forebrain cholinergic neurons express the GABA synthetic enzyme Gad2 and the vesicular GABA transporter (Slc32a1). We confirmed the direct release of GABA by knocking out Slc32a1 from cholinergic neurons. Our results identify GABA as an overlooked fast neurotransmitter utilized throughout the forebrain cholinergic system. GABA/ACh corelease may have major implications for modulation of cortical function by cholinergic neurons.

Article and author information

Author details

  1. Arpiar Saunders

    Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Adam J Granger

    Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bernardo L Sabatini

    Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    For correspondence
    bernardo_sabatini@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experimental manipulations were performed in accordance with a protocol (#03551) approved by the Harvard Standing Committee on Animal Care following guidelines described in the US National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Publication history

  1. Received: January 9, 2015
  2. Accepted: February 26, 2015
  3. Accepted Manuscript published: February 27, 2015 (version 1)
  4. Version of Record published: March 24, 2015 (version 2)

Copyright

© 2015, Saunders et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 7,219
    Page views
  • 1,692
    Downloads
  • 122
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Arpiar Saunders
  2. Adam J Granger
  3. Bernardo L Sabatini
(2015)
Corelease of acetylcholine and GABA from cholinergic forebrain neurons
eLife 4:e06412.
https://doi.org/10.7554/eLife.06412
  1. Further reading

Further reading

    1. Neuroscience
    Andrew P Davison, Shailesh Appukuttan
    Insight

    Artificial neural networks could pave the way for efficiently simulating large-scale models of neuronal networks in the nervous system.

    1. Neuroscience
    Jonathan Nicholas, Nathaniel D Daw, Daphna Shohamy
    Research Article

    A key question in decision making is how humans arbitrate between competing learning and memory systems to maximize reward. We address this question by probing the balance between the effects, on choice, of incremental trial-and-error learning versus episodic memories of individual events. Although a rich literature has studied incremental learning in isolation, the role of episodic memory in decision making has only recently drawn focus, and little research disentangles their separate contributions. We hypothesized that the brain arbitrates rationally between these two systems, relying on each in circumstances to which it is most suited, as indicated by uncertainty. We tested this hypothesis by directly contrasting contributions of episodic and incremental influence to decisions, while manipulating the relative uncertainty of incremental learning using a well-established manipulation of reward volatility. Across two large, independent samples of young adults, participants traded these influences off rationally, depending more on episodic information when incremental summaries were more uncertain. These results support the proposal that the brain optimizes the balance between different forms of learning and memory according to their relative uncertainties and elucidate the circumstances under which episodic memory informs decisions.