Cited by 203Neuroscience and Neuropharmacology ResearchNicotinic Acetylcholine Receptors StudyNeural dynamics and brain function

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Corelease of acetylcholine and GABA from cholinergic forebrain neurons

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Saunders, Arpiar, Granger, Adam J, Sabatini, Bernardo L·2015·eLife

DOI 10.7554/elife.06412PMC PMC4371381

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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 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.

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Figure 1. Optogenetic stimulation of cortical Chat+ fibers evokes fast, monosynaptic GABAA receptor-mediated currents. (A) Low-magnification view of sagittal section from Chat i-Cre; Rosa26 lsl-ChR2-EYFP mouse forebrain. ChR2-EYFP (green) is expressed in the nucleus basalis (NB), globus pallidus externus (GP), striatum and cortex (Ctx). (B) Higher-magnification view of ChR2-EYFP expression combined with ChAT immunostaining (magenta) in frontal cortex (top) and nucleus basalis (bottom). Arrowheads indicate cells immunopositive for ChAT. (C) Example 2-photon stack from a layer 1 interneuron following whole-cell recording and dialysis with Alexa Fluor 594. (D) High-magnification view of ChR2-EYFP+ somata and fibers in layers 1 and 2/3 of frontal cortex. NeuN immunostain (magenta) highlights the distribution of neuronal somata across layers. Arrowhead indicates an example layer 1 interneuron surrounded by ChR2-EYFP fibers. (E) Example PSCs from voltage-clamp recordings of three different layer 1 interneurons in response to blue light stimulation (blue bar) of ChR2+ cholinergic fibers. Neurons were voltage-clamped at −70 mV (left) to isolate EPSCs or at 0 mV (middle and right) to isolate IPSCs. PSCs recorded in the presence of glutamate receptor antagonists CPP and NBQX are shown in black and after bath application of nAChR antagonists (MEC, MLA, and DHβE) in red. (F) Example light-evoked IPSCs from a layer 1 interneuron in a Chat i-Cre; Rosa26 lsl-ChR2-EYFP mouse voltage-clamped at 0 mV in the presence of CPP and NBQX (baseline) and following subsequent bath application of (from left to right) nAChR antagonists, TTX, 4AP, and SR95531. (G) Summary graph of IPSC peaks normalized to baseline (n = 5 cells from 4 mice). Asterisk, condition vs baseline p < 0.05, Mann–Whitney test). (H) Onset latencies for monosynaptic nEPSCs (n = 41 cells), monosynaptic IPSCs (n = 9 cells), and polysynaptic IPSCs (n = 19 cells from 9 mice). Mean (±sem) are shown in green. Asterisk, p < 0.05, Mann–Whitney test. DOI: http://dx.doi.org/10.7554/eLife.06412.003CC BY · PubMed Central

Figure 2. Immunopositive ChAT cells in the forebrain express Slc32a1. (A) Top, sagittal and coronal schematic views of a mouse brain showing cholinergic regions of interest. Red boxes indicate approximate locations for magnified regions below. Bottom, example single-plane image from a confocal stack from sections of a Slc32a1i-Cre; Rosa26 lsl-zsGreen mouse immunostained for ChAT (magenta) and reporting Cre expression (green). Ctx, cortex; GP, globus pallidus externus; NB, nucleus basalis; MS/DBB, medial septum/diagonal band of broca; PPN, pedunculopontine nucleus. Insets show magnified view of individual neurons indicated by the white arrowhead. (B) Quantification of colocalization between cells expressing zsGreen Cre reporter and ChAT immunostain by brain region (zsGreen+/ChAT+, from 3 mice: Ctx, 628/628; GP, 238/243; NB, 598/624; MS/DBB, 560/601; PPN, 3/157). DOI: http://dx.doi.org/10.7554/eLife.06412.004CC BY · PubMed Central

Figure 3. Immunopositive ChAT cells in the forebrain express Gad2. (A) Top, sagittal and coronal schematic views of a mouse brain showing cholinergic regions of interest. Red boxes indicate approximate locations for magnified regions below. Bottom, example single-plane image from a confocal stack from sections of a Gad2 i-Cre; Rosa26 lsl-zsGreen mouse immunostained for ChAT (magenta) and reporting Cre expression (green). Ctx, cortex; GP, globus pallidus externus; NB, nucleus basalis; MS/DBB, medial septum/diagonal band of broca; PPN, pedunculopontine nucleus. Insets show magnified view of individual neurons indicated by the white arrowhead. (B) Quantification of colocalization between cells expressing zsGreen Cre reporter and ChAT immunostain by brain region (zsGreen+/ChAT+, from 4 mice: Ctx, 518/519; GP, 273/372; NB, 860/934;MS/DBB, 673/685; PPN, 6/110). DOI: http://dx.doi.org/10.7554/eLife.06412.005CC BY · PubMed Central

Figure 3—figure supplement 1. Immunopositive ChAT cells of the cortex but not major subcortical projections express Gad1. (A) Top, sagittal and coronal schematic views of a mouse brain showing cholinergic regions of interest. Red boxes indicate approximate locations for magnified regions below. Bottom, example single-plane image from a confocal stack from sections of a Gad1GFP (green) mouse immunostained for ChAT (magenta). Ctx, cortex; GP, globus pallidus externus; NB, nucleus basalis; MS/DBB, medial septum/diagonal band of broca; PPN, pedunculopontine nucleus. Insets show magnified view of individual neurons indicated by the white arrowhead. (B) Quantification of colocalization between cells expressing GFP and ChAT immunostain by brain region (GFP+/ChAT+, from 4 mice: Ctx, 122/135; GP, 7/413; NB, 0/439;MS/DBB, 1/573; PPN, 12/246). DOI: http://dx.doi.org/10.7554/eLife.06412.006CC BY · PubMed Central

Figure 4. GABA release from cortical ChAT+ axons requires Slc32a1. (A) Example light-evoked nEPSCs and IPSCs from four different layer 1 interneurons voltage-clamped at −70 or 0 mV from Chat i-Cre; Rosa26 lsl-ChR2-EYFP mice with wild-type cholinergic neurons (Slc32a1+/+) or conditional Slc32a1 knock-out (Slc32a1fl/fl). (B) Top, the number and proportion of layer 1 interneurons in which light-evoked nEPSCs or direct IPSCs were detected from Chat i-Cre; Rosa26 lsl-ChR2-EYFP mice with wild-type Slc32a1 alleles (Slc32a1+/+, from 2 mice) or following conditional Slc32a1 knock-out (Slc32a1fl/fl, from 4 mice). Bottom, PSC peaks for each condition. Means (±sem) are shown in green. DOI: http://dx.doi.org/10.7554/eLife.06412.007CC BY · PubMed Central

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Authors: Saunders, A., Granger, A. J., & Sabatini, B. L.
Affiliations: Howard Hughes Medical Institute (US)
Corresponding author: Sabatini, Bernardo L
ORCID: Saunders, Arpiar
Granger, Adam J
Sabatini, Bernardo L
Venue: eLife
Publisher: eLife Sciences Publications, Ltd
Published: 2015-02-27
Volume: 4
ISSN: 2050-084X (ISSN-L)
DOI: 10.7554/elife.06412
PMC: PMC4371381
OpenAlex: W2142530108
Cited by: 200
References: 45
Citations by year: 2026: 5 · 2025: 17 · 2024: 12 · 2023: 18 · 2022: 21 · 2021: 19 · 2020: 20 · 2019: 24 · 2018: 24 · 2017: 18 · 2016: 19 · 2015: 3
FWCI: 9.95
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
creativecommons.org/licenses/by/4.0/ (am)
creativecommons.org/licenses/by/4.0/ (tdm)
Locations: eLife (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institute of Neurological Disorders and Stroke (NINDS) (#NS072030)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords: acetylcholine, GABA, cholinergic neurons, forebrain, GABAA receptor, nicotinic acetylcholine receptors, choline acetyltransferase, channelrhodopsin, layer 1 interneurons, GAD-2, vesicular GABA transporter, synaptic signaling
MeSH terms: Acetylcholine, Animals, Choline O-Acetyltransferase, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Membrane Potentials, Mice, Transgenic, Synaptic Transmission, Receptors, GABA-A, Receptors, Nicotinic, Tetrodotoxin, 4-Aminopyridine, Prosencephalon, Patch-Clamp Techniques, Microscopy, Confocal, Excitatory Postsynaptic Potentials, Potassium Channel Blockers, Sodium Channel Blockers, Microscopy, Fluorescence, Multiphoton, Vesicular Inhibitory Amino Acid Transport Proteins, Cholinergic Neurons

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Corelease of acetylcholine and GABA from cholinergic forebrain neurons

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