Dual-transmitter neurons: functional implications of co-release and co-transmission

Abstract

Co-transmission, the ability of a neuron to release multiple transmitters, has long been recognized in selected circuits. However, the release of multiple primary neurotransmitters from a single neuron is only beginning to be appreciated. Here we consider recent examples of co-transmission as well as co-release-the packaging of multiple neurotransmitters into a single vesicle. The properties associated with each mode of release greatly enhance the possible action of such neurons within circuits. The functional importance of dual- (or multi-) transmitter neurons extends beyond actions on postsynaptic receptors, due in part to differential spatial and temporal profiles of each neurotransmitter. Recent evidence also suggests that the dual-transmitter phenotype can be dynamically regulated during development and following injury or disease.

Figure 1. Co-transmission in the sympathetic nervous system

Stimulation of a sympathetic ganglion neuron revealed (a) a fast, nicotinic EPSP (left) and higher stimulation evoked an action potential (right). (b and c)Such stimuli can also elicit a slow muscarinic IPSP (b) or EPSP (c) depending on the stimulation conditions. (d) Strong stimulation generated a late slow EPSP consistent with co-transmission by the neuromodulator LHRH. Note timescale difference in each panel. Adapted from Figure 1 of Jan et al., 1979.

Figure 2. Co-release and Co-transmission are distinct modes of release

(a) With co-release, both neurotransmitters (mixed red and blue) are packaged into the same set of synaptic vesicles. Upon an action potential invading the presynaptic terminal, vesicles containing both neurotransmitters are released into the synaptic cleft. (b) In contrast, co-transmission requires neurotransmitters be sequestered into distinct populations of synaptic vesicles with differential release mediated by differential Ca²⁺ sensitivities (left panel). For example, a single action potential might release one set of vesicles (red), but multiple action potentials might be required to release both sets of vesicles (red and blue). Alternatively, co-transmission can rely on spatial segregation of vesicle populations to different boutons (right panel) in which case, unique information is transmitted to different postsynaptic targets.

Figure 3. Functional considerations of different classes of co-released transmitters

Different classes of dual-transmitter neurons have distinct functional implications for circuit dynamics. (a) The effect of neurons that release two fast-acting neurotransmitters (such as GABA and Glycine) is primarily determined by the postsynaptic receptors; including (1) the kinetics and amplitude of the postsynaptic current, (2) the specific receptor types expressed in the postsynaptic neuron and (3) the synaptic or extrasynaptic location of postsynaptic receptors. (b) For neurons that release a fast-acting neurotransmitter and a monoamine, additional factors that determine the functional output include (4) second messenger cascades and intrinsically slower currents, such as GIRK and (5) modulation of the presynaptic terminal. (c) The action of neurons that release a fast-acting neurotransmitter and a neuromodulator include (6) direct receptor modulation, (7) postsynaptic changes in gene expression and (8) trophic support.