Presynaptic control of inhibitory neurotransmitter content in VIAAT containing synaptic vesicles

• GABA and glycine compete for uptake into synaptic vesicles by a shared vesicular inhibitory amino acid transporter called VIAAT or vGAT.
• The present dogma states that GABA and glycine are released from single synaptic vesicles in direct proportion to their concentration in the presynaptic cytosol.
• This review examines the experimental evidence concerning GABA/glycine accumulation into synaptic vesicles.
• Together, the data implies that the GABA/glycine content of vesicles may be carefully regulated, perhaps at the level of each presynaptic terminal.
• Changes in vesicle content at inhibitory terminals may be a form of medium-term presynaptic plasticity.

In mammals, fast inhibitory neurotransmission is carried out by two amino acid transmitters, γ-aminobutyric acid (GABA) and glycine. The higher brain uses only GABA, but in the spinal cord and brain stem both GABA and glycine act as inhibitory signals. In some cases GABA and glycine are co-released from the same neuron where they are co-packaged into synaptic vesicles by a shared vesicular inhibitory amino acid transporter, VIAAT (also called vGAT). The vesicular content of all other classical neurotransmitters (eg. glutamate, monoamines, acetylcholine) is determined by the presence of a specialized vesicular transporter. Because VIAAT is non-specific, the phenotype of inhibitory synaptic vesicles is instead predicted to be dependent on the relative concentration of GABA and glycine in the cytosol of the presynaptic terminal. This predicts that changes in GABA or glycine supply should be reflected in vesicle transmitter content but as yet, the mechanisms that control GABA versus glycine uptake into synaptic vesicles and their potential for modulation are not clearly understood.This review summarizes the most relevant experimental data that examines the link between GABA and glycine accumulation in the presynaptic cytosol and the inhibitory vesicle phenotype. The accumulated evidence challenges the hypothesis that vesicular phenotype is determined simply by the competition of inhibitory transmitter for VIAAT and instead suggest that the GABA/glycine balance in vesicles is dynamically regulated.