Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Osaka, Japan.
Department of Biological Sciences, Graduate School of Science, Osaka University, Osaka, Japan.
PLoS One. 2021 Nov 12;16(11):e0258364. doi: 10.1371/journal.pone.0258364. eCollection 2021.
Importin α1/KPNA1 is a member of the Importin α family widely present in the mammalian brain and has been characterized as a regulator of neuronal differentiation, synaptic functionality, and anxiety-like behavior. In humans, a de novo mutation of the KPNA1 (human Importin α5) gene has been linked with schizophrenia; however, the precise roles of KPNA1 in disorder-related behaviors are still unknown. Moreover, as recent studies have highlighted the importance of gene-environment interactions in the development of psychiatric disorders, we investigated the effects of Kpna1 deletion and social isolation stress, a paradigm that models social stress factors found in human patients, on psychiatric disorder-related behaviors in mice. Through assessment in a behavioral battery, we found that Kpna1 knockout resulted in the following behavioral phenotype: (1) decreased anxiety-like behavior in an elevated plus maze test, (2) short term memory deficits in novel object recognition test (3) impaired sensorimotor gating in a prepulse inhibition test. Importantly, exposure to social isolation stress resulted in additional behavioral abnormalities where isolated Kpna1 knockout mice exhibited: (1) impaired aversive learning and/or memory in the inhibitory avoidance test, as well as (2) increased depression-like behavior in the forced swim test. Furthermore, we investigated whether mice showed alterations in plasma levels of stress-associated signal molecules (corticosterone, cytokines, hormones, receptors), and found that Kpna1 knockout significantly altered levels of corticosterone and LIX (CXCL5). Moreover, significant decreases in the level of prolactin were found in all groups except for group-housed wild type mice. Our findings demonstrate that Kpna1 deletion can trigger widespread behavioral abnormalities associated with psychiatric disorders, some of which were further exacerbated by exposure to adolescent social isolation. The use of Kpna1 knockout mice as a model for psychiatric disorders may show promise for further investigation of gene-environment interactions involved in the pathogenesis of psychiatric disorders.
Importin α1/KPNA1 是 Importin α 家族的成员，广泛存在于哺乳动物的大脑中，其被认为是神经元分化、突触功能和焦虑样行为的调节剂。在人类中，KPNA1（人类 Importin α5）基因的从头突变与精神分裂症有关；然而，KPNA1 在与疾病相关的行为中的确切作用仍不清楚。此外，由于最近的研究强调了基因-环境相互作用在精神疾病发展中的重要性，我们研究了 Kpna1 缺失和社会隔离应激对小鼠与精神疾病相关行为的影响，社会隔离应激是一种模拟人类患者中发现的社会应激因素的范式。通过行为测试，我们发现 Kpna1 敲除导致以下行为表型：（1）在高架十字迷宫测试中焦虑样行为减少，（2）在新物体识别测试中短期记忆缺陷，（3）在条件性回避测试中感觉运动门控受损。重要的是，暴露于社会隔离应激会导致额外的行为异常，其中孤立的 Kpna1 敲除小鼠表现出：（1）在抑制性回避测试中，厌恶学习和/或记忆受损，以及（2）在强迫游泳测试中，抑郁样行为增加。此外，我们研究了小鼠是否表现出与应激相关信号分子（皮质酮、细胞因子、激素、受体）的血浆水平改变，发现 Kpna1 敲除显著改变了皮质酮和 LIX（CXCL5）的水平。此外，除了群居野生型小鼠外，所有组的催乳素水平都显著降低。我们的研究结果表明，Kpna1 缺失会引发广泛的与精神疾病相关的行为异常，其中一些异常在暴露于青少年社会隔离后进一步加重。Kpna1 敲除小鼠作为精神疾病模型的使用可能为进一步研究涉及精神疾病发病机制的基因-环境相互作用提供希望。
