Mechanisms and functions of GABA co-release

Abstract

The 'one neuron, one neurotransmitter' doctrine states that synaptic communication between two neurons occurs through the release of a single chemical transmitter. However, recent findings suggest that neurons that communicate using more than one classical neurotransmitter are prevalent throughout the adult mammalian CNS. In particular, several populations of neurons previously thought to release only glutamate, acetylcholine, dopamine or histamine also release the major inhibitory neurotransmitter GABA. Here, we review these findings and discuss the implications of GABA co-release for synaptic transmission and plasticity.

Figure 1. Distinct cellular and molecular mechanisms of co-transmission

Although it is often difficult to identify co-transmission experimentally using electrophysiological and anatomical approaches, there are several possible mechanisms by which co-transmission of two neurotransmitters might occur, each offering distinct functionality and plasticity. a|The transmitters may be loaded into individual synaptic vesicles using a common vesicular transporter. The abundance of the transmitters in the cytosol and transporter affinity for those transmitters will determine the relative content of synaptic vesicles. Such co-packaging ensures that both transmitters are released at the same time and location, and are subject to similar presynaptic short-term plasticity. b|The transmitters may be packaged into individual vesicles using distinct vesicular transporters. The relative abundance of each co-transmitter in vesicles varies with cytosolic transmitter availability and with the expression levels of the vesicular transporters. Unless all vesicles express both transporters, this type of co-packaging likely occurs together with the co-packaging described in part c. c| The transmitters may be packaged into separate vesicles that are found within individual presynaptic boutons. Although both transmitters would be exocytosed from the same presynaptic bouton, their release could be modulated independently over short and long time scales, depending on transmitter abundances, synaptic vesicle release probability and the rate of synaptic vesicle recycling and loading for each transmitter. d|The transmitters may be packaged into separate vesicles that distribute to distinct presynaptic release sites. Physical separation would allow the presynaptic release of both transmitters to be modulated separately, and the targeting of each transmitter to different postsynaptic compartments. For example, glutamate release may target dendritic spines while GABA is exocytosed onto dendritic shafts. e|An example of transmitter co-release that does not result in synaptic co-transmission is depicted, in which postsynaptic membranes (cell A and cell B) express receptors for only one of the two transmitters. This mechanism enables presynaptic neurons to broadcast a signal that is differentially interpreted by distinct neuronal elements.

Figure 2. Functions of GABA co-release

a|Once released in the synaptic cleft, GABA can signal pre- and postsynaptically, homo- and heterosynaptically and via ionotropic GABA receptors type A (GABA_A) and GABA receptor type C (GABA_C) and metabotropic GABA_B receptors. Gating of GABA_A and GABA_C receptors shunts synaptic conductances by decreasing input resistance (R_in). Net flow of Cl⁻ through these receptors alters the membrane potential (V_m), which affects Ca²⁺ influx through voltage-gated Ca²⁺ channels (VGCCs) and NMDA receptors. GABA_B receptors act to inhibit presynaptic exocytosis and postsynaptic depolarization through modulation of voltage gated potassium channels (VGKCs), VGCCs and the presynaptic release machinery. b|Depending on the Cl⁻ reversal potential (E_Cl) relative to the resting membrane potential (V_rest) of a neuron, GABA co-release may dampen cellular excitability by physically hyperpolarizing postsynaptic membranes (top) or by shunting synaptic depolarizations (bottom). To illustrate this, the postsynaptic potentials evoked by presynaptic release of glutamate only, GABA only and co-release of glutamate and GABA are depicted. c|GABA release can exert a depolarizing influence if the post-synaptic cell expresses hyperpolarization-activated channels that depolarize membranes (top) or if intracellular Cl⁻ is elevated, such that E_Cl lies above V_rest (bottom). Each example depicts fluctuations in membrane potential upon stimulation of a presynaptic GABAergic synapse (asterisk denotes truncated action potential). d|Co-transmission can be directed in space to achieve synergistic effects in complex neuronal circuits. Three cortical microcircuits are shown under different conditions, each composed of a pyramidal neuron, a local inhibitory interneuron and an excitatory afferent. Under baseline conditions (left), excitatory afferent stimulation evokes three spikes in the pyramidal cell. Target-specific co-release of GABA at some synapses, but not others, enables basal forebrain neurons to enhance (middle) and TMN neurons to dampen (right) the output of pyramidal cells. e|GABA co-release provides a temporally precise signal. Schematic representation of the spontaneous action potential discharge of a target cell under baseline conditions (top), or upon stimulation of afferents that co-release GABA along with a neuromodulator that increases membrane excitability by activating GPCRs (middle and bottom). Phasic inhibition of action potential firing by GABA co-release (the phasic inhibitory influence shown in blue) allows the postsynaptic cell to readily distinguish between single and burst stimulation of presynaptic afferents.