Importin ?5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1.
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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 ? knockout lines revealed that reduced expression of importin ?5 (KPNA1) in hippocampal neurons specifically decreases anxiety in mice. Re-expression of importin ?5 in ventral hippocampus of knockout animals increased anxiety behaviors to wild-type levels. Hippocampal neurons lacking importin ?5 reveal changes in presynaptic plasticity and modified expression of MeCP2-regulated genes, including sphingosine kinase 1 (Sphk1). Knockout of importin ?5, but not importin ?3 or ?4, reduces MeCP2 nuclear localization in hippocampal neurons. A Sphk1 blocker reverses anxiolysis in the importin ?5 knockout mouse, while pharmacological activation of sphingosine signaling has robust anxiolytic effects in wild-type animals. Thus, importin ?5 influences sphingosine-sensitive anxiety pathways by regulating MeCP2 nuclear import in hippocampal neurons.
SUBMITTER: Panayotis N
PROVIDER: S-EPMC6302549 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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