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Cellular distribution of the NMDA-receptor activated synapto-nuclear messenger Jacob in the rat brain

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Abstract

In previous work, we found that the protein messenger Jacob is involved in N-methyl-d-aspartate receptor (NMDAR) signaling to the nucleus and cAMP response element-binding protein (CREB) mediated gene expression in hippocampal primary neurons. Particularly, extrasynaptic NMDAR activation drives Jacob efficiently into the nucleus where it then induces gene expression that promotes neurodegeneration. However, the protein also translocates to the nucleus in CA1 neurons after Schaffer collateral long-term potentiation (LTP) but not long-term depression (LTD), suggesting that Jacob might be involved in hippocampal and LTP-dependent learning and memory processes. Not much is known about the cellular and subcellular distribution of the protein in brain. In this paper, we provide an overview of the expression of Jacob in rat brain with special emphasis on the hippocampus. We show that Jacob is abundant in hippocampal pyramidal neurons and interneurons but absent from astrocytes and microglia. Interestingly, we found that Jacob is also present in mossy fiber axons. Double immunofluorescence confocal laser scans with presynaptic markers demonstrate that Jacob is indeed found at excitatory but not inhibitory presynaptic sites. Accordingly, we found no substantial co-localization of Jacob with a postsynaptic marker of inhibitory synapses, gephyrin. In contrast, almost all postsynaptic density protein 95 (PSD-95) positive excitatory postsynaptic sites also exhibited strong Jacob-immunofluorescence. Taken together, these data support a synaptic and nuclear role of Jacob that implicates long-distance NMDAR signaling to the nucleus in excitatory neurons.

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Acknowledgments

The authors gratefully acknowledge the professional technical assistance of C. Borutzki, S. Hochmuth and M. Marunde; S. Bera for assistance with ICC experiments. This work was supported by grants of the Deutsche Forschungsgemeinschaft; Grant number SFB779 TPB8; SFB854 TP7, Kr1879 3-1 (to M.R.K.), a DIP grant (to M.R.K), EU FP7 MC-ITN NPlast, CBBS (to A.K.) National Science Foundation China; Grant number 30870795, 30970920 (to T.B.), and the Schram Foundation (to M.R.K). M.M. is recipient of a European Molecular Biology Organization (EMBO) Long-Term Fellowship (EMBO ALTF 884-2011) co-funded by the European Commission (EMBOCOFUND2010, GA-2010-267146) and Marie Curie Actions.

Conflict of interest

The authors declare that they have no conflict of interest.

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Author notes

  1. Philipp Bethge

    Present address: CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 3000, Bordeaux, France

Authors and Affiliations

  1. RG Neuroplasticity, Leibniz Institute for Neurobiology, Brenneckestr. 6, 39118, Magdeburg, Germany

    Marina Mikhaylova, Anna Karpova, Julia Bär, Philipp Bethge & Michael R. Kreutz

  2. Cell Biology, Faculty of Science, Utrecht University, Rm. Z.523, H.R. Kruytgebouw Padualaan 8, 3584CH, Utrecht, The Netherlands

    Marina Mikhaylova

  3. Institutes of Brain Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, DongAn Road 130, 200032, Shanghai, People’s Republic of China

    PingAn YuanXiang, Ying Chen & Thomas Behnisch

  4. SL Electron and Laserscanning Microscopy, Leibniz Institute for Neurobiology, Magdeburg, Germany

    Werner Zuschratter

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  1. Marina Mikhaylova
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  2. Anna Karpova
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Correspondence to Michael R. Kreutz.

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Mikhaylova, M., Karpova, A., Bär, J. et al. Cellular distribution of the NMDA-receptor activated synapto-nuclear messenger Jacob in the rat brain. Brain Struct Funct 219, 843–860 (2014). https://doi.org/10.1007/s00429-013-0539-1

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