GABAergic-like dopamine synapses in the brain

Abstract

\n Dopaminergic axons originate in the midbrain and establish widely spread synapses throughout the brain. Synaptic transmission at these synapses plays a crucial role for volitional movement and reward-related behaviors, while dysfunction of dopamine (DA) synapses causes various psychiatric and neurological disorders. Despite this significance, the true nature of brain-wide spatial and functional features of DA synapses remains poorly understood due to difficulties defining functional DA synapses at the molecular and physiological levels. Here we show that DA synapses are structured and function like GABAergic synapses in the mouse brain with marked regional heterogeneity. DA transmission is strongly correlated with GABA co-transmission at DA synapses across the brain areas. In addition, functional DA synapses possess GABAergic postsynaptic markers and are unevenly distributed throughout the brain with distinct spatial clustering. In the dorsal striatum, GABAergic-like DA synapses are uniquely clustered on the dendrites and GABA transmission at DA synapses has disparate physiological properties. Remarkably, the attenuation of GABA co-transmission precedes deficits in dopaminergic transmission in animal model of Parkinsonism. Our findings unravel distinct spatial and functional nature of GABAergic-like DA synapses in health and disease. Furthermore, the broader implication of our results is that GABAergic-like features of DA synapses can be utilized to better understand the real complexity of synaptic actions at DA synapses in regulating neural circuits.