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

Axons of dopaminergic neurons express gamma-aminobutyric acid type-A receptors (GABARs) and nicotinic acetylcholine receptors (nAChRs) which are both independently positioned to shape striatal dopamine release. Using electrophysiology and calcium imaging, we investigated how interactions between GABARs and nAChRs influence dopaminergic axon excitability. Direct axonal recordings showed that benzodiazepine application suppresses subthreshold axonal input from cholinergic interneurons (CINs). In imaging experiments, we used the first temporal derivative of presynaptic calcium signals to distinguish between direct- and nAChR-evoked activity in dopaminergic axons. We found that GABAR antagonism with gabazine selectively enhanced nAChR-evoked axonal signals. Acetylcholine release was unchanged in gabazine suggesting that GABARs located on dopaminergic axons, but not CINs, mediated this enhancement. Unexpectedly, we found that a widely used GABAR antagonist, picrotoxin, inhibits axonal nAChRs and should be used cautiously for striatal circuit analysis. Overall, we demonstrate that GABARs on dopaminergic axons regulate integration of nicotinic input to shape presynaptic excitability.