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

Lead Research Organisation: King's College London
Department Name: Neuroscience

Abstract

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.

Technical Summary

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.

Publications

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Easton AC (2013) aCaMKII autophosphorylation controls the establishment of alcohol drinking behavior. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Killick R (2009) Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. in Biochemical and biophysical research communications

 
Description BBSRC project grant
Amount £442,078 (GBP)
Funding ID BB/J021423/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2013 
End 03/2016
 
Description EC Marie Curie Fellowship
Amount £112,222 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Charity/Non Profit
Country Global
Start 01/2006 
End 01/2008
 
Title CaMKIIN AAVs 
Description recombinant AAVs to masnipulate the expression of endogenous CaMKII inhibitor proteins. We are currently testing the usefulness of these AAVs. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This research material will be instrumental for determining the functions of endogenous CaMKII inhibitor proteins and it might shed new insights into mechanisms of memory storage. We are currently performing pilot studies and depending on the results we may apply for follow up funding from the MRC for further research. 
 
Title Camkk mutants 
Description The mutants are suitable to study the role of CaMKK (calcium/calmodulin kinase kinases) dependent signalling 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2006 
Provided To Others? Yes  
Impact These mutants were valuable for studying the role of synaptic kinases in learning and memory. 
 
Description CaMKII autophosphorylation and addiction 
Organisation Mount Sinai Hospital (USA)
Department Fishberg Department of Neuroscience
Country United States 
Sector Hospitals 
PI Contribution Role of CaMKII autophosphorylation in ethanol and cocaine addiction. We provide CaMKII mutant mice for this collaboration. Collaborators are: Drs. Eric Nestler (USA) and Christian Muller (Germany).
Impact At this stage we have obtained some results; it is too early to present these findings at conferences or in papers.
Start Year 2009
 
Description CaMKII autophosphorylation and inhibitory LTP 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided intellectual insights and knock-in mutant mice.
Collaborator Contribution Synergistic interactions on the role of CaMKII in synaptic plasticity.
Impact Publication: PMID: 17884930
 
Description CaMKII autophosphorylation and late CA1 LTP 
Organisation University of Mons
Department Department of Neurosciences
Country Belgium 
Sector Academic/University 
PI Contribution Studies of late CA1 LTP in the absence of CaMKII autophosphorylation. We provide mutant mice and intellectual input.
Impact We obtained some results but need to do more experiments before data can be disseminated.
Start Year 2010
 
Description CaMKII autophosphorylation and synapse formation 
Organisation Open University
Department Department of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Studies of the role of CaMKII autophosphorylation in hippocampal synaptogenesis during memory formation
Impact We have some results and are close to submit a publication.
Start Year 2010
 
Description Role of CaMKII autophosphorylation for place cells 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided knock-in mutant mice and intellectual input.
Collaborator Contribution Synergistic insights for the role of CaMKII signalling in spatial learning and memory.
Impact Publication: PMID: 17634379
 
Description Role of CaMKII autophosphorylation for plasticity in spinal cord 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided CaMKII knock-in mutant mice and intellectual input.
Collaborator Contribution Synergistic insights into synaptic plasticity mechanisms.
Impact Publication: PMID: 16875841
 
Description Role of CaMKII autophosphorylation for spine growth 
Organisation University College London
Department Neuroscience, Physiology & Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided knock-in mutant mice and intellectual insights.
Collaborator Contribution Synergistic insight on the synaptic function of CaMKII
Impact Publication: PMID: 17202430
 
Description The role of CaMKII autophosphorylation in DG LTP 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided mutant mice for the LTP recordings and we analysed the phosphorylation of synaptic signalling molecules after LTP induction.
Collaborator Contribution Our synergistic interactions advanced insights into synaptic plasticity mechanisms
Impact Publication in 2006: PMID: 16728448