The fundamental variables of small-molecule–neuropeptide co-transmission, including the potential degrees of freedom at particular presynaptic and postsynaptic profiles, and the impact of presynaptic neuron firing rate, modulatory state and extracellular peptidase activity, act to increase the complexity of synaptic transmission.
There is considerable diversity in the consequences for synaptic transmission resulting from small-molecule–neuropeptide co-transmission at identified synapses, and their impact on behaviour. One highlight is that the various mechanisms by which this co-transmission influences synapses (for example, convergent or divergent co-transmission, firing rate-dependent co-transmitter release, and so on) are shared across invertebrate and vertebrate species.
Using exogenously applied neuropeptides has provided many insights into their modulatory actions, but this approach also has limitations and can lead to erroneous conclusions, as illustrated by studies in the crustacean stomatogastric ganglion that compare the influence of exogenous versus neuronally released neuropeptides from identified neurons.
Extending small-molecule–neuropeptide co-transmission studies from individual synapses to their impact on microcircuits, results from the crustacean stomatogastric system are presented to elucidate the impact of convergent versus divergent co-transmission, to separate regulation of co-transmitters and to show the distinct influence on the same microcircuits of different neurons with shared co-transmitters.
Work from the stomatogastric system is also used to provide insight regarding the imperfect match between the influence of apparently equivalent, small-molecule–neuropeptide co-transmitting neurons on the same microcircuits in different species.
Colocalization of small-molecule and neuropeptide transmitters is common throughout the nervous system of all animals. The resulting co-transmission, which provides conjoint ionotropic ('classical') and metabotropic ('modulatory') actions, includes neuropeptide- specific aspects that are qualitatively different from those that result from metabotropic actions of small-molecule transmitter release. Here, we focus on the flexibility afforded to microcircuits by such co-transmission, using examples from various nervous systems. Insights from such studies indicate that co-transmission mediated even by a single neuron can configure microcircuit activity via an array of contributing mechanisms, operating on multiple timescales, to enhance both behavioural flexibility and robustness.
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Research in the authors' laboratories is funded by the US National Institutes of Health (NIH) grant NS-29436 (MPN), NSF grant IOS-1153417 (D.M.B.) and NIH grant NS17813 (E.M.).
The authors declare no competing financial interests.
- Biogenic amines
Amine-containing neurotransmitters (dopamine, histamine, 5-hydroxytryptamine (vertebrates and invertebrates), noradrenaline (vertebrates) and octopamine (invertebrates)) that commonly, but not exclusively, act via G protein- coupled receptors to evoke metabotropic responses.
- Stomatogastric ganglion
(STG). A small, well-defined ganglion in the decapod crustacean (for example, crabs and lobsters) stomatogastric nervous system containing 25–30 neurons (depending on species), nearly all of which contribute to one or both microcircuits (gastric mill circuit (chewing), pyloric circuit (pumping and filtering of chewed food)) located therein.
- Postsynaptic convergence (of co-transmitters)
Multiple neurotransmitters released from the same neuron that bind to their respective receptors on the same postsynaptic neuron to regulate neuronal activity.
- Presynaptic convergence (of co-transmitters)
Multiple neurotransmitters released from the same neuron that bind to their respective receptors on the same presynaptic terminal (or terminals) to regulate neurotransmitter release from said terminal (or terminals).
Defines the phase of chewing when the teeth move apart; during the crab or lobster gastric mill rhythm, retraction defines the phase of neuronal activity in the sole interneuron (Int1) and the motor neurons (for example, DG neuron) that drive contraction of the 'retractor' muscles, which cause the teeth to move away from midline in the intact animal.
Defines the phase of chewing when the teeth come together; during the crab or lobster gastric mill rhythm, protraction defines the phase of neuronal activity in the motor neurons (for example, LG neuron) that drive contraction of the 'protractor' muscles, which cause the teeth to come together at the midline in the intact animal.
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Nusbaum, M., Blitz, D. & Marder, E. Functional consequences of neuropeptide and small-molecule co-transmission. Nat Rev Neurosci 18, 389–403 (2017). https://doi.org/10.1038/nrn.2017.56
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