GABAergic-like dopamine synapses in the brain

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 a significant portion of dopamine synapses are structured and function like GABAergic synapses with marked regional heterogeneity, which we call GABAergic-like dopamine synapses. In addition, GABAergic-like dopamine synapses show lower clustered patterns compared to conventional GABAergic synapses on striatal spiny projection neuron dendrites. Interestingly, 6 weeks knockdown of neuroligin-2, a key postsynaptic protein at GABAergic synapses, unexpectedly does not weaken GABA co-transmission but instead temporarily facilitates it at dopamine synapses in the striatal neurons. As expected, longer periods of neuroligin-2 knockdown (12 weeks) show significantly decreased GABA co-transmission. More importantly, the attenuation of GABA co-transmission precedes deficits in dopaminergic transmission and changes in dopamine synapses in animal models of Parkinsonism. Our findings reveal unknown spatial and functional nature of GABAergic-like dopamine synapses in health and disease.