Presynaptic GABAA receptors control integration of nicotinic input onto dopaminergic axons in the striatum

Axons of dopaminergic neurons express gamma-aminobutyric acid type-A receptors (GABA_ARs) and nicotinic acetylcholine receptors (nAChRs), which are positioned to shape striatal dopamine release. We examine how interactions between GABA_ARs and nAChRs influence dopaminergic axon excitability. Axonal patch-clamp recordings reveal that potentiation of GABA_ARs by benzodiazepines suppress dopaminergic axon responses to cholinergic interneuron transmission. In imaging experiments, we use the first temporal derivative of axonal calcium signals to distinguish between direct stimulation of dopaminergic axons and nAChR-evoked activity. Inhibition of GABA_ARs with gabazine selectively enhance nAChR-evoked axonal calcium signals but does not alter the strength or dynamics of acetylcholine release, suggesting that the enhancement is mediated primarily by GABA_ARs on dopaminergic axons. Unexpectedly, we find that a widely used GABA_AR antagonist, picrotoxin, inhibits axonal nAChRs and should be used cautiously for striatal circuit analysis. Overall, we demonstrate that GABA_ARs on dopaminergic axons regulate integration of nicotinic input to shape axonal excitability.