Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway
Yusuke Sakai,
Haiyan Li,
Hiromichi Inaba,
Yuki Funayama,
Erina Ishimori,
Ayako Kawatake-Kuno,
Hirotaka Yamagata,
Tomoe Seki,
Teruyuki Hobara,
Shin Nakagawa,
Yoshifumi Watanabe,
Susumu Tomita,
Toshiya Murai,
Shusaku Uchida
Affiliations
Yusuke Sakai
SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Haiyan Li
SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Hiromichi Inaba
SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Yuki Funayama
SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Erina Ishimori
SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Ayako Kawatake-Kuno
SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Hirotaka Yamagata
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
Tomoe Seki
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
Teruyuki Hobara
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan
Shin Nakagawa
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
Yoshifumi Watanabe
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan
Susumu Tomita
Department of Cellular and Molecular Physiology, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA
Toshiya Murai
SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Shusaku Uchida
SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Hon-cho, Kawaguchi, Saitama 332-0012, Japan; Corresponding author
Summary: Although stressful events predispose individuals to psychiatric disorders, such as depression, not all people who undergo a stressful life experience become depressed, suggesting that gene-environment interactions (GxE) determine depression risk. The ventral hippocampus (vHPC) plays key roles in motivation, sociability, anhedonia, despair-like behaviors, anxiety, sleep, and feeding, pointing to the involvement of this brain region in depression. However, the molecular mechanisms underlying the cross talk between the vHPC and GxE in shaping behavioral susceptibility and resilience to chronic stress remain elusive. Here, we show that Ca2+/calmodulin-dependent protein kinase IIβ (CaMKIIβ) activity in the vHPC is differentially modulated in GxE mouse models of depression susceptibility and resilience, and that CaMKIIβ-mediated TARPγ-8 phosphorylation enhances the expression of AMPA receptor subunit GluA1 in the postsynaptic sites to enable stress resilience. We present previously missing molecular mechanisms underlying chronic stress-elicited behavioral changes, providing strategies for preventing and treating stress-related psychiatric disorders.
