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

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 w...

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Autores principales:	Koki Sakurai, Taichi Itou, Makiko Morita, Emiko Kasahara, Tetsuji Moriyama, Tom Macpherson, Takaaki Ozawa, Yoichi Miyamoto, Yoshihiro Yoneda, Atsuo Sekiyama, Masahiro Oka, Takatoshi Hikida
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4a9eaea0a57543f4bf73cf1afa647241
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spelling	oai:doaj.org-article:4a9eaea0a57543f4bf73cf1afa6472412021-12-02T20:13:14ZEffects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.1932-620310.1371/journal.pone.0258364https://doaj.org/article/4a9eaea0a57543f4bf73cf1afa6472412021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0258364https://doaj.org/toc/1932-6203Importin 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.Koki SakuraiTaichi ItouMakiko MoritaEmiko KasaharaTetsuji MoriyamaTom MacphersonTakaaki OzawaYoichi MiyamotoYoshihiro YonedaAtsuo SekiyamaMasahiro OkaTakatoshi HikidaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0258364 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Koki Sakurai Taichi Itou Makiko Morita Emiko Kasahara Tetsuji Moriyama Tom Macpherson Takaaki Ozawa Yoichi Miyamoto Yoshihiro Yoneda Atsuo Sekiyama Masahiro Oka Takatoshi Hikida Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.
description	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.
format	article
author	Koki Sakurai Taichi Itou Makiko Morita Emiko Kasahara Tetsuji Moriyama Tom Macpherson Takaaki Ozawa Yoichi Miyamoto Yoshihiro Yoneda Atsuo Sekiyama Masahiro Oka Takatoshi Hikida
author_facet	Koki Sakurai Taichi Itou Makiko Morita Emiko Kasahara Tetsuji Moriyama Tom Macpherson Takaaki Ozawa Yoichi Miyamoto Yoshihiro Yoneda Atsuo Sekiyama Masahiro Oka Takatoshi Hikida
author_sort	Koki Sakurai
title	Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.
title_short	Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.
title_full	Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.
title_fullStr	Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.
title_full_unstemmed	Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.
title_sort	effects of importin α1/kpna1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/4a9eaea0a57543f4bf73cf1afa647241
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Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.

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