Disrupting phosphorylation of Tyr-1070 at GluN2B selectively produces resilience to depression-like behaviors
Xiaofang Shi,
Qi Zhang,
Jie Li,
Xingyu Liu,
Yi Zhang,
Minhua Huang,
Weiqing Fang,
Junyu Xu,
Tifei Yuan,
Lin Xiao,
Yi-Quan Tang,
Xiao-Dong Wang,
Jianhong Luo,
Wei Yang
Affiliations
Xiaofang Shi
NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, 310058, P.R. China
Qi Zhang
Department of Biophysics, Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, P.R. China
Jie Li
NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, 310058, P.R. China
Xingyu Liu
Department of Biophysics, Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, P.R. China
Yi Zhang
Department of Biophysics, Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, P.R. China
Minhua Huang
Department of Biophysics, Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, P.R. China
Weiqing Fang
Department of Pharmacy, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, P.R. China
Junyu Xu
NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, 310058, P.R. China
Tifei Yuan
Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
Lin Xiao
Institute for Brain Research and Rehabilitation, South China Normal University, Key Laboratory of Brain Cognition and Education Sciences, Ministry of Education, 510631 Guangzhou, China
Yi-Quan Tang
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
Xiao-Dong Wang
Department of Neurobiology and Department of Psychiatry of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China
Jianhong Luo
NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine and the MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, 310058, P.R. China; Corresponding author
Wei Yang
Department of Biophysics, Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, P.R. China; Corresponding author
Summary: Drugs targeting N-methyl-D-aspartate receptors (NMDARs) have been approved to treat major depressive disorder (MDD); however, the presence of undesirable psychotomimetic and cognitive side effects may limit their utility. In this study, we show that the phosphorylation levels of the GluN2B subunit at tyrosine (Y) 1070 increase in mice after both acute and chronic restraint stress (CRS) exposure. Preventing GluN2B-Y1070 phosphorylation via Y1070F mutation knockin produces effects similar to those of antidepressants but does not affect cognitive or anxiety-related behaviors in subject mice. Mechanistically, the Y1070F mutation selectively reduces non-synaptic NMDAR currents and increases the number of excitatory synapses in the layer 5 pyramidal neurons of medial prefrontal cortex (mPFC) but not in the hippocampus. Altogether, our study identifies phosphorylation levels of GluN2B-Y1070 in the mPFC as a dynamic, master switch guarding depressive behaviors, suggesting that disrupting the Y1070 phosphorylation of GluN2B subunit has the potential for developing new antidepressants.
