Kinase-dead knock-in mouse reveals an essential role of kinase activity of Ca2+/calmodulin-dependent protein kinase IIα in dendritic spine enlargement, long-term potentiation, and learning

Abstract

Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) is an essential mediator of activity-dependent synaptic plasticity that possesses multiple protein functions. So far, the autophosphorylation site-mutant mice targeted at T286 and at T305/306 have demonstrated the importance of the autonomous activity and Ca 2+/calmodulin-binding capacity of CaMKIIα, respectively, in the induction of long-term potentiation (LTP) and hippocampus-dependent learning. However, kinase activity of CaMKIIα, the most essential enzymatic function, has not been genetically dissected yet. Here, we generated a novel CaMKIIα knock-in mouse that completely lacks its kinase activity by introducing K42R mutation and examined the effects on hippocampal synaptic plasticity and behavioral learning. In homozygous CaMKIIα (K42R) mice, kinase activity was reduced to the same level as in CaMKIIα-null mice, whereas CaMKII protein expression was well preserved. Tetanic stimulation failed to induce not only LTP but also sustained dendritic spine enlargement, a structural basis for LTP, at the Schaffer collateral-CA1 synapse, whereas activity-dependent postsynaptic translocation of CaMKIIα was preserved. In addition, CaMKIIα (K42R) mice showed a severe impairment in inhibitory avoidance learning, a form of memory that is dependent on the hippocampus. These results demonstrate that kinase activity of CaMKIIα is a common critical gate controlling structural, functional, and behavioral expression of synaptic memory. Copyright © 2009 Society for Neuroscience.