title: The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength.
abstract: Learning, memory, and cognition are thought to require normal long-term potentiation (LTP) of synaptic strength, which in turn requires binding of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B. For LTP induction, many additional required players are known. Here we tested the hypothesis that CaMKII/GluN2B binding also mediates the more elusive maintenance of synaptic strength. Intriguingly, the CaMKII inhibitor tatCN21 reduces synaptic strength only at high concentrations necessary for CaMKII/NMDAR disruption (20 μm) but not at lower concentrations sufficient for kinase inhibition (5 μm). However, increased concentration also causes unrelated effects. Thus, to distinguish between correlation and causality, we used a pharmacogenetic approach. In a mouse with a mutant NMDAR GluN2B subunit that is CaMKII binding-incompetent, any tatCN21 effects that are specific to the CaMKII/GluN2B interaction should be abolished, and any remaining tatCN21 effects have to be nonspecific (i.e. mediated by other targets). The results showed that the persistent reduction of synaptic strength by transient application of 20 μm tatCN21 had a nonspecific presynaptic component (on fiber volley amplitude) that was unrelated to the CaMKII/GluN2B interaction or CaMKII activity. However, the remaining component of the persistent tatCN21 effect was almost completely abolished in the GluN2B mutant mouse. These results highlight the requirement for stringent pharmacogenetic approaches to separate specific on-target effects from nonspecific off-target effects. Importantly, they also demonstrate that the CaMKII/GluN2B interaction is required not only for normal LTP induction but also for the maintenance of synaptic strength.
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Barcomb
authors.affiliation: the Department of Pharmacology, School of Medicine, University of California, Davis, California 95616.
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Hell
authors.affiliation: Pediatrics, Section of Neurology, School of Medicine, University of Colorado Denver, Aurora, Colorado 80045 and.
authors.forename: Tim A
authors.initials: TA
authors.lastname: Benke
authors.affiliation: From the Departments of Pharmacology and ulli.bayer@ucdenver.edu.
authors.forename: K Ulrich
authors.initials: KU
authors.lastname: Bayer
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: C121001:NR2B NMDA receptor; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C000616211:tatCN21 peptide; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Ca2+/calmodulin-dependent protein kinase II (CaMKII); N-methyl-d-aspartate receptor (NMDA receptor, NMDAR); glutamate receptor; hippocampus; synapse