Corelease of acetylcholine and GABA from cholinergic forebrain neurons

Saunders, Arpiar; Granger, Adam J.; Sabatini, Bernardo L.

doi:10.7554/elife.06412

Cited by 183 publications

(203 citation statements)

References 46 publications

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“…We cannot exclude the possibility that optogenetic stimulation triggered corelease of other neurotransmitters from cholinergic terminals (25), or that mechanisms secondary to cholinergic stimulation are essential for mediating the behavioral effects described here (26). However, in addition to results from our electrochemical recordings studies (18,19), a considerable literature on the effects of pharmacological manipulations of the cholinergic system on attentional performance in animals and humans (27)(28)(29) is consistent with the present attribution of a cholinergic mechanism underlying the effects of optogenetic stimulation on cue detection processes (as defined in the introduction).…”

Section: Discussionmentioning

confidence: 99%

Cortical cholinergic signaling controls the detection of cues

Gritton

Howe

Mallory

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

184

208

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The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.V irtually all cortical regions and layers receive inputs from cholinergic neurons originating in the nucleus basalis of Meynert, the substantia innominata, and the diagonal band of the basal forebrain (BF). Reflecting the seemingly diffuse organization of this projection system, functional conceptualizations traditionally have described acetylcholine (ACh) as a neuromodulator that influences broadly defined behavioral and cognitive processes such as wakefulness, arousal, and gating of input processing (1, 2). However, anatomical studies have revealed a topographic organization of BF cholinergic cell bodies with highly segregated cortical projection patterns (3-7). Such an anatomical organization favors hypotheses describing the cholinergic mediation of discrete cognitive-behavioral processes. Studies assessing the behavioral effects of cholinergic lesions, recording from or stimulating BF neurons in behaving animals have supported such hypotheses, proposing that cholinergic activity enhances sensory coding and mediates the ability of reward-predicting stimuli to control behavior (8-17).In separate experiments using two different tasks, we reported the presence of phasic cholinergic release events (transients) in the medial prefrontal cortex (mPFC) of rodents trained to report the presence of cues (18,19). These studies used choline-sensitive microelectrodes to measure changes in extracellular choline concentrations that reflect the hydrolysis of newly released ACh by endogenous acetylcholinesterase (SI Results and Discussion). Importantly, such cholinergic transients were not observed in trials in which cues were missed and in which the absence of a cue was correctly reported and rewarded. Cho...

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Section: Discussionmentioning

confidence: 99%

Cortical cholinergic signaling controls the detection of cues

Gritton

Howe

Mallory

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

184

208

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“…Since neurons express more than one transmitter, do they switch singly or perhaps in sets, and are there preferred switch partners? A related issue concerns the relationship of transmitter switching to transmitter coexpression and corelease that have now been widely observed (Gillespie et al, 2005; Hnasko and Edwards, 2012; Shabel et al, 2014; Nelson et al, 2014; Saunders et al, 2015). Perhaps coexpression arises when the molecular machinery of switching stalls in midstride or has been arrested.…”

Section: Perspectivesmentioning

confidence: 99%

Neurotransmitter Switching? No Surprise

Spitzer¹

2015

Neuron

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Among the many forms of brain plasticity, changes in synaptic strength and changes in synapse number are particularly prominent. However, evidence for neurotransmitter respecification or switching has been accumulating steadily, both in the developing nervous system and in the adult brain, with observations of transmitter addition, loss, or replacement of one transmitter with another. Natural stimuli can drive these changes in transmitter identity, with matching changes in postsynaptic transmitter receptors. Strikingly, they often convert the synapse from excitatory to inhibitory or vice versa, providing a basis for changes in behavior in those cases in which it has been examined. Progress has been made in identifying the factors that induce transmitter switching and in understanding the molecular mechanisms by which it is achieved. There are many intriguing questions to be addressed.

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“…In the CNS, we have recently described an instance of functional ACh and GABA cotransmission onto interneurons in cortical layer 1 (Saunders et al, 2015a). Selective activation of cholinergic axons in cortex using channelrhodopsin (ChR2) evoked both ACh-mediated excitatory postsynaptic currents (EPSCs) and GABA-mediated inhibitory postsynaptic currents (IPSCs) in layer 1 interneurons.…”

Section: Functional Demonstrations Of Ach/gaba Cotransmissionmentioning

confidence: 99%

“…The proportion of layer 1 interneurons that receive GABAergic or cholinergic inputs differ significantly, with many cells receiving one of the inputs but not the other (Saunders et al, 2015a). This is suggestive of separate vesicle populations for each neurotransmitter, but could also be explained by differences in postsynaptic expression of nAChRs and GABA receptors.…”

Section: Functional Demonstrations Of Ach/gaba Cotransmissionmentioning

confidence: 99%

Cotransmission of acetylcholine and GABA

et al. 2016

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Neurons that produce acetylcholine (ACh) are positioned to broadly influence the brain, with axonal arborizations that extend throughout the cerebral cortex, striatum, and hippocampus. While the action of these neurons has typically been attributed entirely to ACh, neurons often release more than one primary neurotransmitter. Here, we review evidence for the cotransmission of the inhibitory neurotransmitter GABA from cholinergic neurons throughout the mammalian central nervous system. Functional cotransmission of ACh and GABA has been reported in the retina and cortex, and anatomical studies suggest that GABA cotransmission is a common feature of nearly all forebrain ACh-producing neurons. Further experiments are necessary to confirm the extent of GABA cotransmission from cholinergic neurons, and the contribution of GABA needs to be considered when studying the functional impact of activity in ACh-producing neurons.

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Corelease of acetylcholine and GABA from cholinergic forebrain neurons

Cited by 183 publications

References 46 publications

Cortical cholinergic signaling controls the detection of cues

Cortical cholinergic signaling controls the detection of cues

Neurotransmitter Switching? No Surprise

Cotransmission of acetylcholine and GABA

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