GABAergic-like dopamine synapses in the brain

Abstract

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 the dysfunction of dopamine synapses causes various psychiatric and neurological disorders. Despite this significance, the true nature of brain-wide spatial and functional features of dopamine synapses remains poorly understood due to difficulties defining functional dopamine synapses at the molecular and physiological levels. Here we show that dopamine synapses are structured and function like GABAergic synapses in the mouse brain with marked regional heterogeneity. Dopamine transmission is strongly correlated with GABA co-transmission at dopamine synapses across the brain areas. In addition, functional dopamine synapses possess GABAergic postsynaptic markers and are unevenly distributed throughout the brain with distinct spatial clustering. In the dorsal striatum, GABAergic-like dopamine synapses are uniquely clustered on the dendrites and GABA transmission at dopamine synapses has disparate physiological characteristics. Importantly, knockdown of the inhibitory cell adhesion molecule in the postsynaptic striatal neurons unexpectedly did not weaken but instead facilitated GABA transmission at dopamine synapses. Lastly, the attenuation of GABA co-transmission precedes defects in dopaminergic transmission in an animal model of Parkinsonism. Our findings unravel distinct spatial and functional nature of GABAergic-like dopamine synapses in health and disease. Furthermore, the broader implication of our results is that GABAergic-like features of dopamine synapses can be utilized to better understand the real complexity of synaptic actions at dopamine synapses in regulating neural circuits.