Axonal GABAA receptors depolarize presynaptic terminals and facilitate transmitter release in cerebellar Purkinje cells

In neurons of the adult brain, somatodendritic GABA(A) receptors (GABA(A)Rs) mediate fast synaptic inhibition and play a crucial role in synaptic integration. GABA(A)Rs are not only present in the somatodendritic compartment, but also in the axonal compartment where they modulate action potential (AP) propagation and transmitter release. Although presynaptic GABA(A)Rs have been reported in various brain regions, their mechanisms of action and physiological roles remain obscure, particularly at GABAergic boutons. Here, using a combination of direct whole-bouton or perforated patch-clamp recordings and local GABA photolysis in single axonal varicosities of cerebellar Purkinje cells, we investigate the subcellular localization and functional role of axonal GABA(A)Rs both in primary cultures and acute slices. Our results indicate that presynaptic terminals of PCs carry GABA(A)Rs that behave as auto-receptors; their activation leads to a depolarization of the terminal membrane after an AP due to the relatively high cytoplasmic Cl- concentration in the axon, but they do not modulate the AP itself. Paired recordings from different terminals of the same axon show that the GABA(A)R-mediated local depolarizations propagate substantially to neighbouring varicosities. Finally, the depolarization mediated by presynaptic GABA(A)R activation augmented Ca2+ influx and transmitter release, resulting in a marked effect on short-term plasticity. Altogether, our results reveal a mechanism by which presynaptic GABA(A)Rs influence neuronal computation. GABA(A) receptors have been described in the axonal compartment of neurons; contrary to dendritic GABA(A) receptors, axonal GABA(A) receptors usually induce depolarizing responses. In this study we describe the presence of functional axonal GABA(A) receptors in cerebellar Purkinje cells by using a combination of direct patch-clamp recordings from the axon terminals and laser GABA photolysis. In Purkinje cells, axonal GABA(A) receptors are depolarizing and induce an increase in neurotransmitter release that results in a change of short-term synaptic plasticity. These results contribute to our understanding of the cellular mechanisms of action of axonal GABA(A) receptors and highlight the importance of the presynaptic compartment in neuronal computation.