Direction of action of presynaptic GABA receptors is highly dependent on the level of receptor activation.

Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABA receptors. However, reports of the functional consequences of presynaptic GABA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABA receptors in mice. Activation of GABA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABA receptors reduces GABA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABA receptor function across synapses. GABA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABA receptors fine-tune synaptic transmission.