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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.

Author information

1
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
2
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
3
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
4
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.
5
Institute of Biochemistry, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
6
Department of Molecular Biology, Integrative Brain Research Center - Ariel, Ariel University, Ariel 40700, Israel.
7
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: mike.fainzilber@weizmann.ac.il.

Abstract

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.

KEYWORDS:

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

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