Abstract
The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are believed to contribute to brain structural plasticity that underlies memory formation. Indeed, the attachment of long chains of PSA to the glycoprotein NCAM down-regulates its adhesive properties by altering cell–cell interactions. In the brain, the biosynthesis of PSA is catalyzed by two polysialyltransferases, which are differentially regulated during lifespan. One of them, ST8SiaIV (PST), is predominantly expressed during adulthood whereas the other one, ST8SiaII (STX), dominates during embryonic and post-natal development. To understand the role played by ST8SiaIV during learning and memory and its underlying hippocampal plasticity, we used knockout mice deleted for the enzyme ST8SiaIV (PST-ko mice). At adult age, PST-ko mice show a drastic reduction of PSA-NCAM expression in the hippocampus and intact hippocampal adult neurogenesis. We found that these mice display impaired long-term but not short-term memory in both, spatial and non-spatial behavioral tasks. Remarkably, memory deficits of PST-ko mice were abolished by exposure to environmental enrichment that was also associated with an increased number of PSA-NCAM expressing new neurons in the dentate gyrus of these mice. Whether the presence of a larger pool of immature, likely plastic, new neurons favored the rescue of long-term memory in PST-ko mice remains to be determined. Our findings add new evidence to the role played by PSA in memory consolidation. They also suggest that PSA synthesized by PST critically controls the tempo of new neurons maturation in the adult hippocampus.
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Acknowledgments
This work was supported by grants from the EU FrameWorkProgram 6 LSHM-CT-2005-512012 (Integrated project PROMEMORIA) to C.R., by the CNRS and Toulouse University. We thank L. Roybon at Lund University, Sweden for graciously providing the GFP retroviral vector and M. Alonzo, F. Zaidi at Toulouse University 3 for their technical support. We also thank the ABC facility from ANEXPLO for housing mice.
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M. Zerwas and S. Trouche contributed equally.
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Supplementary material 1 Adult hippocampal neurogenesis in PST-ko mice raised in standard housing conditions. Photomicrographs depicting Ki67- (a), DCX- (c) immunoreactive (+) cells (arrowheads) in the DG of PST-ko mice (scale bar = 20 μm). Numbers of proliferating Ki67+ (b), immature DCX+ (d) cells in the DG were the same across all three genotypes. (TIFF 1373 kb)
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Supplementary material 2 Normal migration and morphology of new hippocampal neurons in PST-ko mice. Confocal image depicting typical 28-day-old GFP-labeled (+) new neurons (arrowheads) in the DG of a PST-ko mouse (scale bar = 30 μm) (a). Distribution of GFP+ neurons (in %) within the sub-layers of the DG of PST-wt and PST-ko mice 28 days after viral injection (b). Four-week-old GFP+ neurons of PST-wt and PST-ko mice exhibited similar length of primary dendrite (c) and similar maximal dendritic length (d) (quantified as illustrated by insets above). Data represent mean ± SEM. (SGZ: subgranular zone, GCL: granular cell layer, inner (iGCL), middle (mGCL), outer (oGCL)). (TIFF 908 kb)
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Supplementary material 3 No impact of PST deletion on anxiety, locomotion and exploratory behavior. Mice from all genotypes spent the same amount of time in the open arms of the elevated plus maze (EPM) (a). The total distance moved during free exploration in the open-field was the same for all genotypes (b). Data represent mean values ± SEM. (***p < 0.001). (TIFF 121 kb)
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Supplementary material 4 Similar anxiety, locomotion and exploratory behavior of mice from all genotypes after environmental enrichment. Enriched (EE) mice of all genotypes spent the same amount of time in the open arms of the elevated plus maze (EPM) (a). Noticeably, after enriched mice spent less time on the open arms from the first min onwards with a pronounced decline from the first to the second min. After enrichment, the total distance moved during free exploration in the open-field was the same for all genotypes (b). Data represent mean values ± SEM. (***p < 0.001). (TIFF 140 kb)
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Zerwas, M., Trouche, S., Richetin, K. et al. Environmental enrichment rescues memory in mice deficient for the polysialytransferase ST8SiaIV. Brain Struct Funct 221, 1591–1605 (2016). https://doi.org/10.1007/s00429-015-0991-1
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DOI: https://doi.org/10.1007/s00429-015-0991-1