Importin α5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1

Nicolas Panayotis, Anton Sheinin, Shachar Y. Dagan, Michael M. Tsoory, Franziska Rother, Mayur Vadhvani, Anna Meshcheriakova, Sandip Koley, Letizia Marvaldi, Didi Andreas Song, Eitan Reuveny, Britta J. Eickholt, Enno Hartmann, Michael Bader, Izhak Michaelevski, Mike Fainzilber

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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. Panayotis et al. found decreased anxiety in importin α5 knockout mice. They report that importin α5 influences sphingosine-sensitive anxiety pathways by regulating MeCP2 nuclear import in hippocampal neurons.

Original languageEnglish
Pages (from-to)3169-3179.e7
JournalCell Reports
Volume25
Issue number11
DOIs
StatePublished - 11 Dec 2018

Keywords

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

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