Roger Nicoll, M.D.
Professor
Department of Cellular Molecular Pharmacology
University of California, San Francisco
(October 12, 2017)
The NMDAR/CaMKII Complex is the Master of the PSD Universe
The protein CaMKII is now understood to play a vital role in memory formation. Many questions remain, however, as to the full extent of its role in synaptic function. Doctor Nicoll discussed his work exploring how neurons function without CaMKII in its various forms. His work highlights the importance of CaMKII to the long-term activity needed for memory formation, and the importance of a particular receptor, the NMDAR, in this process.
CaMKII is one of the most studied synaptic proteins, but many critical issues regarding its function in baseline synaptic function and plasticity remain unresolved. Using a CRISPR based system to acutely delete CaMKII and replace it with mutated forms in single neurons, the Nicoll lab has comprehensively and rigorously addressed its various synaptic roles. In brief, basal AMPAR and NMDAR synaptic transmission both require CaMKII, but not CaMKIIβ, indicating that, even in the adult, synaptic transmission is determined by the ongoing action of CaMKII. 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 CaMKII, CaMKIIβ and with the molecular replacement of the kinase dead mutant (T286A). Nicoll concludes that CaMKII fully accounts for NMDAR-dependent LTP. With the exception of NMDAR synaptic currents, all aspects of CaMKII signaling requires binding to the NMDAR, emphasizing the essential role of this receptor as a master synaptic signaling hub.