Dual-transmitter neurons: functional implications of co-release and co-transmission
Introduction
Neurotransmitter phenotype has long been recognized as a hallmark of neuronal identity. The classical view was that each neuron releases a single neurotransmitter, leading to the ‘one neuron, one transmitter’ hypothesis [1], formalized by John Eccles as Dale's Principle [2]. However, we now know that many neurons throughout the brain are capable of releasing two or more neurotransmitters [3, 4, 5]. For simplicity, in this review we refer to these cells as ‘dual’ transmitter neurons. Some of the first evidence for such dual- (or multi-) transmitter neurons was noted in 1979, when Jan et al. reported a very slow synaptic potential in a subset of sympathetic neurons that accompanied the well-established cholinergic transmission (Figure 1) [6]. This slow potential was mediated by a peptide, LHRH (luteinizing hormone-releasing hormone), indicating that the presynaptic neuron released a neuroactive peptide as well as acetylcholine [6, 7]. Such co-transmission, defined broadly as the release of multiple neurotransmitters from a single neuron, has been reported for many neuromodulators including ATP, neuroactive peptides, neurotrophic factors and even ions such as Zn2+ [8, 9, 10, 11, 12, 13, 14, 15]. Recent evidence, however, suggests that neurons can co-transmit not only neuromodulators but also multiple primary neurotransmitters including fast-acting neurotransmitters, monoamines and acetylcholine [16, 17, 18, 19, 20].
Although dual-transmitter neurons are found throughout the brain, the functional significance of co-transmission on neuronal circuits has been difficult to dissect. This difficulty arises, in part, because in addition to activating postsynaptic receptors, co-released neurotransmitters can modulate presynaptic and postsynaptic responses and even modulate the packaging of other neurotransmitters into synaptic vesicles [4]. Additionally, each neurotransmitter may be differentially released in time and space, thereby complicating analysis. A consideration of all these parameters is necessary to understand how dual-transmitter neurons alter the computational capabilities of neuronal circuits. Of note, the functional importance of co-transmission has been better described in select invertebrate systems, where each transmitter can differentially enhance the ability of the circuit to participate in multiple computational tasks [21, 22, 23, 24]. Here we focus on recent studies of dual-transmitter neurons, including the mechanisms governing the release of multiple neurotransmitters, and the functional importance of co-transmission and co-release on circuit function in the mammalian CNS.
Section snippets
Co-release versus co-transmission
The release of multiple neurotransmitters from a single neuron does not necessarily imply co-release, that is that two or more neurotransmitters are packaged into a single population of synaptic vesicles (Figure 2a). Co-transmission can be more broadly defined as the release of multiple neurotransmitters from non-overlapping pools of synaptic vesicles (Figure 2b). The distinction between co-release and co-transmission is important because each mode of release can have different potential
Functional implications of co-release in neuronal circuits
Broadly speaking, there are three classes of dual-transmitter neurons: neurons that release two fast-acting neurotransmitters; neurons that release a fast-acting neurotransmitter and a slow-acting monoamine; and neurons that release a fast-acting neurotransmitter and a neuromodulator, defined here as peptides, ions or other small molecules (Figure 3). Each class can have different effects on presynaptic and postsynaptic neurons, thus altering the functional impact of dual-transmitter neurons
Co-release of GABA and glycine
Release of GABA and glycine from some inhibitory neurons represents a robust example of co-release [16, 37••, 40, 41]. The first physiological evidence of glycine/GABA co-release was reported in the spinal cord, where miniature IPSCs had both GABA and glycine receptor components [16], suggesting that both neurotransmitters were present in single vesicles. Co-release of GABA and glycine is perhaps not surprising given that the vesicular inhibitory amino acid transporter (VIAAT, also known as
Co-release during development
Emerging evidence suggests that the transmitter phenotype of a neuron is plastic. Even in single transmitter neurons, the neurotransmitter phenotype can be dynamically modulated in response to sensory stimuli. For example, in the hypothalamus, neurons can switch from releasing dopamine to somatostatin with changes in photoperiod [66•]. Similarly in dual-transmitter neurons, there is evidence that the transmitter phenotype can change during normal development. In many circuits co-release is
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank all the members of the Westbrook lab for helpful discussion. We also thank Lori Vaskalis for help with illustrations. This work was supported by NIH Grants NS26464 and MH46613 to GLW; as well as a Tartar Trust Fellowship, ARCS Scholarship, and National Science Foundation Graduate Research Fellowship (DGE0925180) to CEV.
References (90)
- et al.
Functional implications of neurotransmitter co-release: glutamate and GABA share the load
Curr Opin Pharmacol
(2006) - et al.
GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism
Eur J Pharmacol
(2011) - et al.
Neuropeptide Y in the dentate gyrus
Prog Brain Res
(2007) - et al.
Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses
Neuron
(2001) Synaptic glutamate release by postnatal rat serotonergic neurons in microculture
Neuron
(1994)- et al.
The roles of co-transmission in neural network modulation
Trends Neurosci
(2001) - et al.
VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse
Ann NY Acad Sci
(2011) - et al.
Vesicular monoamine and glutamate transporters select distinct synaptic vesicle recycling pathways
J Neurosci
(2010) - et al.
Uptake of glycine into synaptic vesicles isolated from rat spinal cord
J Neurochem
(1990) - et al.
Mesoaccumbens dopamine neuron synapses reconstructed in vitro are glutamatergic
Neuroscience
(2000)
Dopamine neurons in culture express VGLUT2 explaining their capacity to release glutamate at synapses in addition to dopamine
J Neurochem
Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus accumbens
J Neurosci
Developmental and target-dependent regulation of vesicular glutamate transporter expression by dopamine neurons
J Neurosci
Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine
J Neurosci
Enhanced sucrose and cocaine self-administration and cue-induced drug seeking after loss of VGLUT2 in midbrain dopamine neurons in mice
J Neurosci
Glutamate decarboxylase 67 is expressed in hippocampal mossy fibers of temporal lobe epilepsy patients
Hippocampus
Adult-born neurons in the olfactory bulb: integration and functional consequences
Curr Top Behav Neurosci
Pharmacology and nerve endings (Walter Ernest Dixon Memorial Lecture): (Section of Therapeutics and Pharmacology)
Proc R Soc Med
Cholinergic and inhibitory synapses in a pathway from motor–axon collaterals to moto-neurons
J Physiol
Co-transmission of dopamine and glutamate
J Gen Physiol
Neurotransmitter corelease: mechanism and physiological role
Annu Rev Physiol
A peptide as a possible transmitter in sympathetic ganglia of the frog
Proc Natl Acad Sci USA
Peptidergic transmission in sympathetic ganglia of the frog
J Physiol
Physiology and pathophysiology of purinergic neurotransmission
Physiol Rev
Opioid modulation of recurrent excitation in the hippocampal dentate gyrus
J Neurosci
Substance P depolarizes striatal projection neurons and facilitates their glutamatergic inputs
J Physiol
Is zinc a neuromodulator?
Sci Signal
Developmentally regulated Ca2+-dependent activator protein for secretion 2 (CAPS2) is involved in BDNF secretion and is associated with autism susceptibility
Cerebellum
Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of spinal cord
Proc Natl Acad Sci USA
Corelease of two fast neurotransmitters at a central synapse
Science
Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum
PLoS ONE
Fast synaptic subcortical control of hippocampal circuits
Science
Presynaptic inhibition selectively weakens peptidergic cotransmission in a small motor system
J Neurophysiol
Neuropeptide feedback modifies odor-evoked dynamics in Caenorhabditis elegans olfactory neurons
Nat Neurosci
Coordination of distinct but interacting rhythmic motor programs by a modulatory projection neuron using different co-transmitters in different ganglia
J Exp Biol
Dopaminergic neurons inhibit striatal output through non-canonical release of GABA
Nature
The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons
J Neurosci
Identification and characterization of the vesicular GABA transporter
Nature
Cloning of functional vesicular GABA and glycine transporter by screening of genome databases
FEBS Lett
Co-release of acetylcholine and gamma-aminobutyric acid by a retinal neuron
Proc Natl Acad Sci USA
Co-release of acetylcholine and GABA by the starburst amacrine cells
J Neurosci
Role of ACh-GABA cotransmission in detecting image motion and motion direction
Neuron
VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety
J Neurosci
Distribution of VGLUT3 in highly collateralized axons from the rat dorsal raphe nucleus as revealed by single-neuron reconstructions
PLoS ONE
Target-dependent use of co-released inhibitory transmitters at central synapses
J Neurosci
Cited by (121)
The neuroendocrine system of Ciona intestinalis Type A, a deuterostome invertebrate and the closest relative of vertebrates
2024, Molecular and Cellular EndocrinologyAlterations in neurotransmitter co-release in Parkinson's disease
2023, Experimental NeurologyPeptidergic and functional delineation of the Edinger-Westphal nucleus
2023, Cell Reports