Biphasic modulation of parallel fibre synaptic transmission by co-activation of presynaptic GABA_A and GABA_B receptors in mice

Key points: Many excitatory synapses co-express presynaptic GABA_A and GABA_B receptors, despite their opposing actions on synaptic transmission. It is still unclear how co-activation of these receptors modulates synapse function. We measured presynaptic GABA receptor function at parallel fibre synapses onto stellate cells in the cerebellum using whole-cell patch-clamp recording and photolytic uncaging of RuBi-GABA. Activation of presynaptic GABA receptors results in a transient (∼100 ms) enhancement of synaptic transmission (mediated by GABA_A receptors) followed by a long lasting (>500 ms) inhibition of transmission (mediated by GABA_B receptors). When activated just prior to high-frequency trains of stimulation, presynaptic GABA_A and GABA_B receptors work together to reduce short-term facilitation/enhance depression, altering the filtering properties of synaptic transmission. Inhibition of synaptic transmission by GABA_B receptors is more sensitive to GABA than enhancement by GABA_A receptors, suggesting GABA_B receptors may be activated by ambient GABA or release from greater distances. Abstract: GABA_A and GABA_B receptors are co-expressed at many presynaptic terminals in the central nervous system. Previous studies have shown that GABA_A receptors typically enhance vesicle release while GABA_B receptors inhibit release. However, it is not clear how the competing actions of these receptors modulate synaptic transmission when co-activated, as is likely in vivo. We investigated this question at parallel fibre synapses in the cerebellum, which co-express presynaptic GABA_A and GABA_B receptors. In acute slices from C57BL/6 mice, we find that co-activation of presynaptic GABA receptors by photolytic uncaging of RuBi-GABA has a biphasic effect on EPSC amplitudes recorded from stellate cells. Synchronous and asynchronous EPSCs evoked within ∼100 ms of GABA uncaging were increased, while EPSCs evoked ∼300–600 ms after GABA uncaging were reduced compared to interleaved control sweeps. We confirmed these effects are presynaptic by measuring the paired-pulse ratio, variance of EPSC amplitudes, and response probability. During trains of high-frequency stimulation GABA_A and GABA_B receptors work together (rather than oppose one another) to reduce short-term facilitation when GABA is uncaged just prior to the onset of stimulation. We also find that GABA_B receptor-mediated inhibition can be elicited by lower GABA concentrations than GABA_A receptor-mediated enhancement of EPSCs, suggesting GABA_B receptors may be selectively activated by ambient GABA or release from more distance synapses. These data suggest that GABA, acting through both presynaptic GABA_A and GABA_B receptors, modulate the amplitude and short-term plasticity of excitatory synapses, a result not possible from activation of either receptor type alone.