Importin α5 regulates anxiety through MeCP2 and sphingosine kinase 1
Authors
- 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
Citation
- Cell Rep 25 (11): 3169-3179
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.