The CaMKII/NMDA receptor complex controls hippocampal synaptic transmission by kinase-dependent and independent mechanisms

Nat Commun. 2018 May 25;9(1):2069. doi: 10.1038/s41467-018-04439-7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cell Membrane / metabolism
  • Female
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / physiology*
  • Humans
  • Long-Term Potentiation / physiology
  • Mice
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / physiology
  • Phosphorylation
  • Rats
  • Receptors, Glutamate / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction / physiology
  • Synapses / physiology
  • Synaptic Transmission / physiology*


  • Receptors, Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2