Corelease of acetylcholine and GABA from cholinergic forebrain neurons

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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 GABA_A 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.

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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.
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.
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.

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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.