Endogenous inhibition of CaMKII: A Novel molecular mechanism to terminate memory formation

What mechanisms are needed to make and store memories in the brain? These mechanisms are still not sufficiently well understood, a fact that prevents us from curing learning and memory deficits in diseases such as mental retardation. My laboratory is studying mechanisms that underlie learning and memory in mice. We perform studies with mice, because in humans we cannot perform well-defined experimental manipulations that are needed to establish mechanisms, and mice are the closest animal species to humans for which a very large repertoire of sophisticated manipulations has been established. We and others have shown that an enzyme called CaMKII is required for the making, but not for the storage, of memory. To terminate the memory making the enzyme needs to be switched off. We have proposed that an endogenous inhibitor protein (CaMKIINalpha) performs this function. More studies are required to validate our hypothesis and here we propose to carry out such studies. If our hypothesis were correct, then follow-up studies will examine whether the novel memory mechanism could be impaired in diseases with associated memory deficits.

One of the main objectives in neurobiology is to understand how the brain forms, stores, and retrieves memories. The current mechanistic understanding of memory processes is still poor and it remains not possible to cure memory deficits in diseases. It is known that the largest component of the post-synaptic density, calcium/calmodulin-dependent kinase II (CaMKII), is an important signalling molecule. CaMKII switches its activity into an autonomous mode upon autophosphorylation. Because of this property CaMKII was believed to be the molecule to mediate memory storage. Recently, we and others have shown that the CaMKII autophosphorylation switch is required for memory formation, but not for memory storage. Ideally, the autonomous CaMKII activity should be stopped after memory formation before the memory storage process begins. However, it is not known how autonomously active CaMKII is switched off to terminate memory formation. Surprisingly, phosphatases do not appear to carry out this function as they are very slow in dephosphorylating autophosphorylated CaMKII. We hypothesized that an endogenous CaMKII inhibitor protein, CaMKIINalpha, blocks autonomously active CaMKII to terminate memory formation. We have preliminary data to support our hypothesis, but further studies are required to test the hypothesis. Here, we propose to study the regulation of CaMKIINalpha at the protein level during memory formation and to investigate whether this regulation terminates autonomous CaMKII activity. Furthermore, we will test whether block of CaMKIINalpha function affects memory formation in hippocampus- and amygdala-dependent behavioural tasks.