Internalization of D2 dopamine receptors is clathrin-dependent and select to dendro-axonic appositions in primate...

Much of our knowledge on trafficking of neurotransmitter receptors derives from heterologous expression systems and neurons in vitro. Understanding these dynamics in vivo for dopamine receptors, and D2 receptors (D2Rs) in particular, presents a foremost challenge as their pharmacological manipulation underlies antipsychotic medications and drug abuse, which may in turn alter response to endogenous dopamine. Here we present the first ultrastructural evidence of clathrin-mediated endocytosis of D2Rs or any other neurotransmitter receptor in the primate brain. We have captured in situ the insertion of D2Rs in clathrin-coated membrane pits, resulting in receptor sorting in primary endosomes. Endocytosis was specific to nonsynaptic membranes of distal dendrites, and virtually absent from larger shafts, spines, axons and perikarya expressing D2Rs. The selective association of D2Rs with the clathrin endocytotic pathway of high-order dendrites identifies a novel substrate for monitoring and adjusting dopaminoception, as well as a potent target for dysregulation, and manipulation, of D2R signalling in mental illness.