Differential Involvement of Kinase Activity of Ca²⁺/Calmodulin-Dependent Protein Kinase IIα in Hippocampus- and Amygdala-Dependent Memory Revealed by Kinase-Dead Knock-in Mouse

Abstract

Ca²⁺/calmodulin-dependent protein kinase IIα (CaMKIIα) is a key mediator of activity-dependent neuronal modifications and has been implicated in the molecular mechanisms of learning and memory. Indeed, several types of CaMKIIα knock-in and knock-out mice revealed impairments in hippocampal synaptic plasticity and behavioral learning. On the other hand, a similar role for CaMKIIα has been implicated in amygdala-dependent memory, but detailed analyses have not much been performed yet. To better understand its involvement in amygdala-dependent memory as compared to hippocampus-dependent memory, here we performed biochemical analyses and behavioral memory tests using the kinase-dead CaMKIIα (K42R) knock-in mouse. In the Morris water maze tasks, homozygous mutants performed well in the visible platform trials, while they failed to form spatial memory in the hippocampus-dependent hidden platform trials. In fear conditioning, these mice were impaired but showed a certain level of amygdala-dependent cued fear memory, which lasted four weeks, while they showed virtually no hippocampus-dependent context discrimination. Neither stronger stimulation nor repetitive stimulation compensated for their memory deficits. The differential outcome of hippocampus- and amygdala-dependent memory in the mutant mouse was not due to differential expression of CaMKIIα between the hippocampus and the amygdala, because biochemical analyses revealed that both kinase activity and protein levels of CaMKII were indistinguishable between the two brain regions. These results indicate that kinase activity of CaMKIIα is indispensable for hippocampus-dependent memory, but not necessarily for amygdala-dependent memory. There may be a secondary, CaMKIIα activity-independent pathway, in addition to the CaMKIIα activity-dependent pathway, in the acquisition of amygdala-dependent memory.

Significance Statement Studying molecular mechanisms of learning and memory is important to confront memory-deficient and abnormal memory-associated disorders. An enzyme called Ca²⁺/calmodulin-dependent protein kinase IIα (CaMKIIα) that is abundant in the brain and phosphorylates important proteins has a key role in such mechanisms. However, how CaMKIIα enzymatic activity is involved in hippocampus- vs. amygdala-dependent memory is still not clear. Using our genetically engineered mouse that lacks kinase activity but retains protein expression of CaMKIIα, here we showed that kinase activity of CaMKIIα is indispensable for hippocampus-dependent space/context-related memory, but not necessarily for amygdala-dependent fear-related memory. The role of CaMKIIα kinase activity in distinguishing different contexts indicates its possible involvement as a measure against abnormal fear memory-associated disorders, such as post-traumatic stress disorder.