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

Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABA_A receptors. However, reports of the functional consequences of presynaptic GABA_A receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABA_A receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABA_A receptors in mice. Activation of GABA_A receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABAB receptors reduces GABA_A receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABA_A receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABA_A 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_A receptor function across synapses. NEW & NOTEWORTHY GABA_A 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_A 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_A receptors fine-tune synaptic transmission.