Importin α5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Anxiety / metabolism*
  • Behavior, Animal
  • Carbolines / pharmacology
  • Hippocampus / pathology
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice, Knockout
  • Neurons / metabolism
  • Phenotype
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Synapses / metabolism
  • Transcription, Genetic
  • alpha Karyopherins / deficiency
  • alpha Karyopherins / metabolism*


  • Anti-Anxiety Agents
  • Carbolines
  • KPNA1 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • alpha Karyopherins
  • FG 7142
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase