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Cell Rep. 2018 Dec 11;25(11):3169-3179.e7. doi: 10.1016/j.celrep.2018.11.066.

Importin α5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1.

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Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Center for Structural and Cellular Biology in Medicine, Institute of Biology, University of Lübeck, 23538 Lübeck, Germany.
Institute of Biochemistry, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Department of Molecular Biology, Integrative Brain Research Center - Ariel, Ariel University, Ariel 40700, Israel.
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:


Importins mediate transport from synapse to soma and from cytoplasm to nucleus, suggesting that perturbation of importin-dependent pathways should have significant neuronal consequences. A behavioral screen on five importin α knockout lines revealed that reduced expression of importin α5 (KPNA1) in hippocampal neurons specifically decreases anxiety in mice. Re-expression of importin α5 in ventral hippocampus of knockout animals increased anxiety behaviors to wild-type levels. Hippocampal neurons lacking importin α5 reveal changes in presynaptic plasticity and modified expression of MeCP2-regulated genes, including sphingosine kinase 1 (Sphk1). Knockout of importin α5, but not importin α3 or α4, reduces MeCP2 nuclear localization in hippocampal neurons. A Sphk1 blocker reverses anxiolysis in the importin α5 knockout mouse, while pharmacological activation of sphingosine signaling has robust anxiolytic effects in wild-type animals. Thus, importin α5 influences sphingosine-sensitive anxiety pathways by regulating MeCP2 nuclear import in hippocampal neurons.


KPNA1; MeCP2; anxiety; anxiolytic; importin; karyopherin; sphingosine kinase; synapse-nucleus communication

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