Importin α5 regulates anxiety through MeCP2 and sphingosine kinase 1

Autor/innen

  • N. Panayotis
  • A. Sheinin
  • S.Y. Dagan
  • M.M. Tsoory
  • F. Rother
  • M. Vadhvani
  • A. Meshcheriakova
  • S. Koley
  • L. Marvaldi
  • D.A. Song
  • E. Reuveny
  • B.J. Eickholt
  • E. Hartmann
  • M. Bader
  • I. Michaelevski
  • M. Fainzilber

Journal

  • Cell Reports

Quellenangabe

  • Cell Rep 25 (11): 3169-3179

Zusammenfassung

  • 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.


DOI

doi:10.1016/j.celrep.2018.11.066