Sustained CaMKII Delta Gene Expression Is Specifically Required for Long-Lasting Memories in Mice

Abstract

Although important information is available on the molecular mechanisms of long-term memory formation, little is known about the processes underlying memory persistence in the brain. Here, we report that persistent gene expression of CaMKIIδ isoform participates in object recognition long-lasting memory storage in mice hippocampus. We found that CaMKIIδ mRNA expression was sustained up to one week after training and paralleled memory retention. Antisense DNA infusion in the hippocampus during consolidation or even after consolidation impairs 7-day- but not 1-day-long memory, supporting a role of CaMKIIδ in memory persistence. CaMKIIδ gene expression was accompanied by long-lasting nucleosome occupancy changes at its promoter. This epigenetic mechanism is described for the first time in a memory process and offers a novel mechanism for persistent gene expression in neurons. CaMKIIδ protein is mainly present in nucleus and presynaptic terminals, suggesting a role in these subcellular compartments for memory persistence. All these results point to a key function of the sustained gene expression of this overlooked CaMKII isoform in long-lasting memories.

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Acknowledgments

We thank Dr. María Eugenia Pedreira and Dr. Damian Refojo for helpful comments on the manuscript. This work was supported by research grants from the National Agency of Scientific and Technological Promotion of Argentina (ANPCyT) PICT2369, National Council of Research (CONICET) PIP5466, and University of Buenos Aires grant X198.

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Correspondence to Noel Federman.

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Supplementary Figure 1.
figure6

CaMKIIδ mRNA Antisense Oligonucleotide design. (a) Diagram showing CaMKIIδ mRNA, its coding sequence and the sequence chosen for the design of the antisense oligonucleotide (ASO) and the scrambled (Scrl) oligonucleotide. (b) Right: Experimental design. Left: Cannulae were guided to CA1 region of the dorsal hippocampus (diagram of a coronal section coupled to a picture showing a coronal slice of a cannulated animal). Arrows indicate sites of infusion. (c). CaMKIIδ mRNA levels relative to Scrl group (nScrl=16, nASO=16, t30,0.05=2.176, p=0.0375 (PNG 1000 kb)

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Zalcman, G., Federman, N., Fiszbein, A. et al. Sustained CaMKII Delta Gene Expression Is Specifically Required for Long-Lasting Memories in Mice. Mol Neurobiol 56, 1437–1450 (2019). https://doi.org/10.1007/s12035-018-1144-3

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Keywords

  • CaMKII
  • Long-term memory
  • Hippocampus
  • Neuroepigenetics
  • Nucleosome occupancy