1. Neuroscience
Download icon

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
Research Article
  • Cited 107
  • Views 7,138
  • Annotations
Cite this article as: eLife 2015;4:e06412 doi: 10.7554/eLife.06412

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

  • 7,138
    Page views
  • 1,613
    Downloads
  • 107
    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)

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

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

  1. Further reading

Further reading

    1. Neuroscience
    Lorenz Deserno et al.
    Research Article Updated

    Dopamine is implicated in representing model-free (MF) reward prediction errors a as well as influencing model-based (MB) credit assignment and choice. Putative cooperative interactions between MB and MF systems include a guidance of MF credit assignment by MB inference. Here, we used a double-blind, placebo-controlled, within-subjects design to test an hypothesis that enhancing dopamine levels boosts the guidance of MF credit assignment by MB inference. In line with this, we found that levodopa enhanced guidance of MF credit assignment by MB inference, without impacting MF and MB influences directly. This drug effect correlated negatively with a dopamine-dependent change in purely MB credit assignment, possibly reflecting a trade-off between these two MB components of behavioural control. Our findings of a dopamine boost in MB inference guidance of MF learning highlight a novel DA influence on MB-MF cooperative interactions.

    1. Developmental Biology
    2. Neuroscience
    Qiuling Li et al.
    Research Article Updated

    Although many genes are known to influence sleep, when and how they impact sleep-regulatory circuits remain ill-defined. Here, we show that insomniac (inc), a conserved adaptor for the autism-associated Cul3 ubiquitin ligase, acts in a restricted period of neuronal development to impact sleep in adult Drosophila. The loss of inc causes structural and functional alterations within the mushroom body (MB), a center for sensory integration, associative learning, and sleep regulation. In inc mutants, MB neurons are produced in excess, develop anatomical defects that impede circuit assembly, and are unable to promote sleep when activated in adulthood. Our findings link neurogenesis and postmitotic development of sleep-regulatory neurons to their adult function and suggest that developmental perturbations of circuits that couple sensory inputs and sleep may underlie sleep dysfunction in neurodevelopmental disorders.