Drosophila long-term memory formation involves regulation of cathepsin activity

Abstract

Whereas short-term memory lasts from minutes to hours, long-term memory (LTM) can last for days or even an entire lifetime. LTM generally forms after spaced repeated training sessions and involves the regulation of gene expression1,2, thereby implicating transcription factors in the initial steps of LTM establishment3. However, the direct participation of effector genes in memory formation has been rarely documented, and many of the mechanisms involved in LTM formation remain to be understood. Here we describe a Drosophila melanogaster mutant, crammer (cer), which shows a specific LTM defect. The cer gene encodes an inhibitor of a subfamily of cysteine proteinases, named cathepsins, some of which might be involved in human Alzheimer's disease4. The Cer peptide was found in the mushroom bodies (MBs), the Drosophila olfactory memory centre and in glial cells around the MBs. The overexpression of cer in glial cells but not in MB neurons induces a decrease in LTM, suggesting that Cer might have a role in glia and that the concentration of the Cer peptide is critical for LTM. In wild-type flies, cer expression transiently decreases after LTM conditioning, indicating that cysteine proteinases are activated early in LTM formation.

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Figure 1: cerP is a specific LTM mutant.
Figure 2: cer encodes a cathepsin inhibitor.
Figure 3: cer is expressed in MB neurons and in glial cells.
Figure 4: The level of cer mRNA is regulated after LTM conditioning.

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Acknowledgements

We thank M.F. Carlier, M. Hertzog and P. Mehlen for advice with biochemistry experiments; S. Brown and C. Talbot for confocal microscopy expertise; and T. Aoki, G. Didelot, G. Isabel and A. Pascual for their comments on this manuscript. This study was supported by a Human Frontier Science Program grant. F.P. was supported by the Ministère de la Recherche and the Fondation des Treilles. D.C. was supported by the Association pour la Recherche sur le Cancer and the European Community Marie Curie Program.

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Correspondence to Thomas Preat.

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Supplementary information

Supplementary Figures

This includes Figure 1 (the memory scores of new cer alleles), Figure 2 (a sequence alignment of Cer with other cathepsin inhibitors, along with a Dixon’s plot showing cathepsin inhibition by Cer) and Figure 3 (the mushroom body expression of the Gal4 line 5122), as well as additional references. (DOC 1773 kb)

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Comas, D., Petit, F. & Preat, T. Drosophila long-term memory formation involves regulation of cathepsin activity. Nature 430, 460–463 (2004). https://doi.org/10.1038/nature02726

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