MEMO_CAMKII · Is CaMKII autophosphorylation a switch to regulate memory consolidation?

Final Activity Report Summary - MEMO_CAMKII (Is CaMKII autophosphorylation a switch to regulate memory consolidation?)

The hippocampus is a part of a forebrain involved in memory formation as well as storing and processing spatial information. The alpha-isoform of the Calcium and calmodulin-dependent kinase II (alpha CaMKII) is the major synaptic protein in glutamateric neurons in the forebrain. Alpha CaMKII activity is regulated by autophosphorylation on the threonine 286. alpha CaMKII T286A mutant mice have impaired NMDAR-dependent LTP in CA1 field of the hippocampus as well as severe deficits in context memory formation. CaMKII T286A mice form fear memory of the context in fear conditioning task only after very intensive training (five shocks). The aim of the project was to understand the molecular basis of memory formation in alphaCaMKII T286A mutant mice. In the first experiment we have confirmed that CaMKII T286A mice learn after five training trials of fear conditioning. In the following experiments, we analysed the expression pattern of commonly used markers of neuronal activity c-Fos, Zif268, Nur77 and JunB proteins after fear conditioning. Importantly, expression of none of those proteins was induced in any of the analysed brain region in T286A mutant mice following fear conditioning. We showed, however, that we could block fear memory in T286A mice giving systemic injection of anisomycin, indicating that fear memory of T286A mice requires protein synthesis de novo. Next, we employed Illumina microarrays and injections of transcription inhibitors into the dorsal hippocampus to answer the question whether fear memory of T286A mice depends of gene expression in the hippocampus and to find relevant genes. Both experiments gave negative results suggesting that there is no memory specific transcription in the hippocampi of T286A mice (comment: we have only investigated one time point), and indicating that fear memory of the context does not depend on transcription in the dorsal hippocampus. In the following experiment, we tested the hypothesis that local translation, using stores of dendritically localised mRNA, may serve as a mechanism of fear memory consolidation in T286A mice. We found that fear conditioning of T286A mice induces expression of locally translated proteins, such as PSD-95 and Arc. Furthermore, we could block fear memory formation in T286A with administration of rapamycin into the dorsal hippocampus. In contrast, wild-type mice did not require local translation in the dorsal hippocampus for contextual fear memory formation. Thus, the T286A have used local translation as a compensation for the absent regulation of immediate-early gene expression. Conclusions: - Long-term context fear memory may be formed in the absence of c-Fos, Zif268, Nur77 and JunB protein expression. - mRNA synthesis in the dorsal hippocampus is not necessary for long-term fear memory formation. - Local translation in the dorsal hippocampus is the mechanism of long-term memory formation in CaMKII T286A mice.

Data: CORDIS, © European Union