Gabaergic-like dopamine synapses in health and parkinson's disease

Abstract

Dopaminergic neurons exist in the midbrain and their axons establish synapses throughout the whole brain. Synaptic transmission at these synapses is crucial for volitional movement and reward-related behaviors, while dysfunction of these synapses causes various psychiatric and neurological disorders. Despite this significance, true biological nature of dopamine synapses remains poorly understood due to difficulties defining functional dopamine synapses at the molecular and physiological levels. Here we show that GABA co-transmission co-exists with dopamine transmission across the brain and a significant portion of dopamine synapses are structured and function like GABAergic synapses with marked regional heterogeneity, which we call GABAergic-like dopamine synapses identified by triple co-localization of tyrosine hydroxylase (TH), bassoon, and neuroligin-2 (NL2). GABAergic-like dopamine synapses show higher density, but lower clustered patterns compared to conventional GABAergic synapses on the dendrites of spiny projection neurons in the dorsal striatum. Moreover, GABA transmission at dopamine synapses has physiological properties distinct from conventional GABA transmission in terms of its calcium channel dependency and quantal properties. Interestingly, 6 weeks knockdown of NL2, a key postsynaptic protein at GABAergic synapses, unexpectedly does not weaken GABA co-transmission but instead temporarily facilitates it at dopamine synapses in striatal neurons. As expected, longer periods of NL2 knockdown (12 weeks) significantly diminishes GABA co-transmission. On the other hand, dopamine transmission and GABAergic-like dopamine synapses are considerably downregulated in both 6 weeks and 12 weeks of NL2 knockdown. More importantly, the attenuation of GABA co-transmission precedes deficits in dopaminergic transmission in animal models of Parkinson’s disease. Our findings reveal unknown 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.