CaMKII is one of the most studied synaptic proteins, but many critical issues regarding its role in synaptic function remain unresolved. Using a CRISPR-based system to delete CaMKII and replace it with mutated forms in single neurons, we have rigorously addressed its various synaptic roles. In brief, basal AMPAR and NMDAR synaptic transmission both require CaMKIIα, but not CaMKIIβ, indicating that, even in the adult, synaptic transmission is determined by the ongoing action of CaMKIIα. While AMPAR transmission requires kinase activity, NMDAR transmission does not, implying a scaffolding role for the CaMKII protein instead. LTP is abolished in the absence of CaMKIIα and/or CaMKIIβ and with an autophosphorylation impaired CaMKIIα (T286A). With the exception of NMDAR synaptic currents, all aspects of CaMKIIα signaling examined require binding to the NMDAR, emphasizing the essential role of this receptor as a master synaptic signaling hub.

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The N‐methyl‐D‐aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate the flux of calcium (Ca2+) into the post‐synaptic compartment. Ca2+ influx subsequently triggers the activation of various intracellular signalling cascades that underpin multiple forms of synaptic plasticity. Functional NMDARs are assembled as heterotetramers composed of two obligatory GluN1 subunits and two GluN2 or GluN3 subunits. Four different GluN2 subunits (GluN2A‐D) are present throughout the central nervous system; however, they are differentially expressed, both developmentally and spatially, in a cell‐ and synapse‐specific manner. Each GluN2 subunit confers NMDARs with distinct ion channel properties and intracellular trafficking pathways. Regulated membrane trafficking of NMDARs is a dynamic process that ultimately determines the number of NMDARs at synapses, and is controlled by subunit‐specific interactions with various intracellular regulatory proteins. Here we review recent progress made towards understanding the molecular mechanisms that regulate the trafficking of GluN2‐containing NMDARs, focusing on the roles of several key synaptic proteins that interact with NMDARs via their carboxyl termini. image