Dopamine synapse is a neuroligin 2 mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures
Significance Nigrostriatal dopaminergic projections form a number of dopamine synapses onto medium spiny neurons in the striatum, and have strong influence on emotion, motivation, voluntary movement, and cognition. Despite the functional importance, the molecular composition at dopamine synapses remains unknown. Here we demonstrate that dopamine synapses are neurochemically mismatched contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. Intriguingly, neuroligin 2 expressed at the GABAergic postsynaptic structure controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Therefore, our findings suggest that neuroligin mediated formation of such neurochemically mismatched synapses could be a novel strategy to increase the target selectivity and potency of modulation by anchoring release sites of neuromodulators to their receptive targets. Midbrain dopamine neurons project densely to the striatum and form so called dopamine synapses on medium spiny neurons (MSNs) principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter 2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin 2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor a1, without any specific clustering of dopamine receptors. Of these, neuroligin 2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin 2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin 2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine sensing targets.
Proceedings of the National Academy of Sciences