Functional consequences of neuropeptide and small-molecule co-transmission

Small-molecule–neuropeptide co-transmission is pervasive throughout the nervous system of all animals. In this Review, Nusbaum, Blitz and Marder discuss how co-transmission is an important source for the considerable flexibility that has been established for synapses, circuits and behaviour. 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.