Synaptic Vesicle Recycling Pathway Determines Neurotransmitter Content and Release Properties.

In contrast to temporal coding by synaptically acting neurotransmitters such as glutamate, neuromodulators such as monoamines signal changes in firing rate. The two modes of signaling have been thought to reflect differences in release by different cells. We now find that midbrain dopamine neurons release glutamate and dopamine with different properties that reflect storage in different synaptic vesicles. The vesicles differ in release probability, coupling to presynaptic Ca2+ channels and frequency dependence. Although previous work has attributed variation in these properties to differences in location or cytoskeletal association of synaptic vesicles, the release of different transmitters shows that intrinsic differences in vesicle identity drive different modes of release. Indeed, dopamine but not glutamate vesicles depend on the adaptor protein AP-3, revealing an unrecognized linkage between the pathway of synaptic vesicle recycling and the properties of exocytosis. Storage of the two transmitters in different vesicles enables the transmission of distinct signals. • Dopamine neurons release glutamate and dopamine with different probability • Coreleased glutamate and dopamine differ in coupling to presynaptic Ca2+ channels • Neurons make two types of synaptic vesicle that differ in response to stimulation • AP-3 is required specifically for formation of synaptic vesicles storing dopamine In this work on glutamate corelease by dopamine neurons, Silm et al. show that an individual neuron expresses two classes of synaptic vesicle that form through distinct mechanisms and transmit distinct information due to differences in frequency dependence. [ABSTRACT FROM AUTHOR]