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

Key points: 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.

Abstract: 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.