The transmitter phenotype of a neuron has long been thought to be stable for the lifespan. Much as eyes have one color and do not change it over time, neurons have been thought to have one neurotransmitter and retain it for their lifetime. Both principles, exclusivity and stability, are challenged by recent data. More and more neurons in different regions of the brain appear to coexpress two or more neurotransmitters. Moreover, the profile of neurotransmitter expression of a given neuron has been shown to change over time, both during development and in response to changes in activity. The present review summarizes recent studies of this neurotransmitter phenotype plasticity (NPP). Homeostatic mechanisms of plasticity are aimed at maintaining the system within a functional range. They appear to be critical for optimal network operations and have been thought to operate largely by regulating intrinsic excitability, synapse number and synaptic strength. NPP provides a new and unexpected level of regulation of network homeostasis. We propose that it provides the basis for NT coexpression and discuss emerging issues and new questions for further studies in coming years.
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