Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice

PLoS One. 2021 Nov 12;16(11):e0258364. doi: 10.1371/journal.pone.0258364. eCollection 2021.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / blood
  • Anxiety / genetics*
  • Behavior, Animal*
  • Chemokine CXCL5 / blood
  • Corticosterone / blood
  • Depression / blood
  • Depression / genetics*
  • Disease Models, Animal
  • Female
  • Learning
  • Male
  • Memory, Short-Term
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prolactin / blood
  • Schizophrenia / blood
  • Schizophrenia / genetics*
  • Signal Transduction / genetics
  • Social Isolation / psychology*
  • alpha Karyopherins / genetics*

Substances

  • Chemokine CXCL5
  • Cxcl5 protein, mouse
  • KPNA1 protein, mouse
  • alpha Karyopherins
  • Prolactin
  • Corticosterone

Grants and funding

This study was supported by the Japan Society for the Promotion of Science KAKENHI grants (JP18K15044 and JP26870341 to T.Moriyama; JP21K15210 to T. Macpherson; JP19K21806, JP19K03385, JP19H01769, JP21H00311 to T.O.; JP16H04789 to Y.Y. and M.O.; JP16H06568, JP18H02542, JP21H05694 to T.H), AMED under Grant Number JP21wm0425010 to T.H., The Sasakawa Scientific Research Grant to K.S., Takeda Life Science Research Foundation to T.O. and T.H., Taiju Life Social Welfare Foundation to T.H., Life Science Foundation of Japan to T.H., The Salt Science Research Foundation, No. 2137 to T.H., No. 2146 to T.O., HOKUTO foundation for the promotion of biological science to T.O., Smoking Research Foundation to T.H., Research Foundation for Opto-science and Technology, The Mitsubishi Foundation to T.O., Kowa Life Science Foundation to T.O., and the Collaborative Research Program of Institute for Protein Research, Osaka University, ICR-21-3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.