NMDA receptors mediate calcium-dependent, bidirectional changes in dendritic PICK1 clustering

AMPA receptor (AMPAR) trafficking at CNS synapses is regulated by several receptor-binding proteins. One model of AMPAR endocytosis entails the cotargeting of the GluR2-interacting protein PICK1 and activated PKC to synapses. We demonstrate that NMDA receptor (NMDAR) activation mediates bidirectional changes in surface AMPARs through two additional forms of PICK1 redistribution. In neurons, NMDAR activation, which induces AMPAR endocytosis, increases endosomal PICK1 clustering. In contrast, stronger NMDAR activation rapidly reduces PICK1 clustering accompanied by decreases in PICK1/GluR2 association and increases in surface AMPAR levels. PICK1-siRNA similarly increases surface AMPARs and occludes the NMDAR-mediated effect, demonstrating the role of PICK1 in this process. Bidirectional NMDAR-mediated changes in PICK1 localization are determined by the magnitude of receptor-activated dendritic calcium signals. Our results show that PICK1 localization in dendrites is subject to multiple forms of regulation that contribute to surface AMPAR expression, likely by modulating the numbers of AMPARs maintained in intracellular compartments.