Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
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.
importins 介导从突触到胞体以及从细胞质到细胞核的运输，这表明 importin 依赖性途径的扰动应该对神经元有重大影响。对五个 importin α 敲除系的行为筛选表明，海马神经元中 importin α5（KPNA1）的表达减少特异性地降低了小鼠的焦虑。在敲除动物的腹侧海马中重新表达 importin α5 将焦虑行为增加到野生型水平。缺乏 importin α5 的海马神经元显示出突触前可塑性的变化和 MeCP2 调节基因的表达改变，包括鞘氨醇激酶 1（Sphk1）。importin α5 的敲除，而不是 importin α3 或 α4 的敲除，减少了海马神经元中 MeCP2 的核定位。Sphk1 阻断剂可逆转 importin α5 敲除小鼠的焦虑缓解，而鞘氨醇信号的药理学激活在野生型动物中具有强大的抗焦虑作用。因此，importin α5 通过调节海马神经元中 MeCP2 的核输入来影响鞘氨醇敏感的焦虑途径。
