Endocytosis following dopamine D₂ receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons

Aberrant dopamine D 2 receptor (D 2 R) activity is associated with neuropsychiatric disorders, making those receptors targets for antipsychotic drugs. Here, we report that novel signaling through the intracellularly localized D 2 R long isoform (D 2L R) elicits extracellular signal-regulated kinase (ERK) activation and dendritic spine formation through Rabex-5/platelet-derived growth factor receptor-β (PDGFRβ)-mediated endocytosis in mouse striatum. We found that D 2L R directly binds to and activates Rabex-5, promoting early-endosome formation. Endosomes containing D 2L R and PDGFRβ are then transported to the Golgi apparatus, where those complexes trigger Gαi3-mediated ERK signaling. Loss of intracellular D 2L R-mediated ERK activation decreased neuronal activity and dendritic spine density in striatopallidal medium spiny neurons (MSNs). In addition, dendritic spine density in striatopallidal MSNs significantly increased following treatment of striatal slices from wild-type mice with quinpirole, a D 2 R agonist, but those changes were lacking in D 2L R knockout mice. Moreover, intracellular D 2L R signaling mediated effects of a typical antipsychotic drug, haloperidol, in inducing catalepsy behavior. Taken together, intracellular D 2L R signaling through Rabex-5/PDGFRβ is critical for ERK activation, dendritic spine formation and neuronal activity in striatopallidal MSNs of mice.