@article{95b06da3158445f9bdf5f15892a68750,
title = "Importin α5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1",
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.",
keywords = "KPNA1, MeCP2, anxiety, anxiolytic, importin, karyopherin, sphingosine kinase, synapse-nucleus communication",
author = "Nicolas Panayotis and Anton Sheinin and Dagan, {Shachar Y.} and Tsoory, {Michael M.} and Franziska Rother and Mayur Vadhvani and Anna Meshcheriakova and Sandip Koley and Letizia Marvaldi and Didi-Andreas Song and Eitan Reuveny and Eickholt, {Britta J.} and Enno Hartmann and Michael Bader and Izhak Michaelevski and Mike Fainzilber",
note = "We thank Alon Chen, Rony Paz, and Avraham Yaron for helpful comments and discussions. We are indebted to Vladimir Kiss, Tali Shalit, and Nitzan Korem for excellent professional and technical assistance and to Yaniv Levi for devoted assistance with animal care. Our research was supported by the European Research Council (AdG Neurogrowth and PoC FAITh), a Simons Explorer Award (#437633), the Chaya Professorial Chair in Molecular Neuroscience (M.F.), the Carolito Stiftung Research Fellow Chair in Neurodegenerative Diseases (M.M.T.), and the French Ministry of Foreign Affairs International Volunteers Program and the Israel Ministry of Immigrant Absorption (N.P.). N.P. performed the behavioral, molecular, and pharmacological experiments and stereotaxic surgeries and imaging. A.S. performed electrophysiological experiments. A.M. performed the FRET assays. N.P. and S.K. performed the subcellular fractionation and western blots. D.-A.S. produced the AAV vectors. N.P., A.S., S.Y.D., A.M., S.K., L.M., M.M.T., F.R., M.V., D.-A.S., B.E., E.R., E.H., M.B., I.M., and M.F. contributed to the concept and design of the experiments. N.P., A.S., S.Y.D., A.M., S.K., L.M., I.M., and M.F. collected, analyzed, or interpreted the data. N.P. and M.F. wrote the manuscript, with input from all coauthors.",
year = "2018",
month = dec,
day = "11",
doi = "https://doi.org/10.1016/j.celrep.2018.11.066",
language = "الإنجليزيّة",
volume = "25",
pages = "3169--3179.e7",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}