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

Abstract

In neurons of the adult brain, somatodendritic GABA_ARs mediate fast synaptic inhibition and play a crucial role in synaptic integration. GABA_ARs 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_ARs 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_ARs both in primary cultures and acute slices. Our results indicate that presynaptic terminals of PCs carry GABA_ARs 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 do not modulate the AP itself. Paired recordings from different terminals of the same axon show that the GABA_AR-mediated local depolarizations propagate substantially to neighboring varicosities. Finally, the depolarization mediated by presynaptic GABA_AR 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_ARs influence neuronal computation.

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