Hai-Yun Zhou1, Jin-Gang He2, Zhuang-Li Hu3, Shi-Ge Xue1, Jun-Feng Xu1, Qian-Qian Cui1, Shuang-Qi Gao1, Bin Zhou1, Peng-Fei Wu3, Li-Hong Long3, Fang Wang4, Jian-Guo Chen5. 1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Laboratory of Neuropsychiatric Diseases, Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Ministry of Education of China, Wuhan, China. 3. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Laboratory of Neuropsychiatric Diseases, Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Ministry of Education of China, Wuhan, China. 4. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Laboratory of Neuropsychiatric Diseases, Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Ministry of Education of China, Wuhan, China. Electronic address: wangfangtj0322@163.com. 5. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Laboratory of Neuropsychiatric Diseases, Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Ministry of Education of China, Wuhan, China. Electronic address: chenj@mails.tjmu.edu.cn.
Abstract
BACKGROUND: The basolateral amygdala (BLA) has been widely implicated in the pathophysiology of major depressive disorder. A-kinase anchoring protein 150 (AKAP150) directs kinases and phosphatases to synaptic glutamate receptors, controlling synaptic transmission and plasticity. However, the role of the AKAP150 in the BLA in major depressive disorder remains poorly understood. METHODS: Depressive-like behaviors in C57BL/6J mice were developed by chronic restraint stress (CRS). Mice received either intra-BLA injection of lentivirus-expressing Akap5 short hairpin RNA or Ht-31, a peptide to disrupt the interaction of AKAP150 and protein kinase A (PKA), followed by depressive-like behavioral tests. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptor (AMPAR)-mediated miniature excitatory postsynaptic currents were recorded by whole-cell patch-clamp techniques. RESULTS: Chronic stress exposure induced depressive-like behaviors, which were accompanied by an increase in total and synaptic AKAP150 expression in the BLA. Accordingly, CRS facilitated the association of AKAP150 with PKA, but not of calcineurin in the BLA. Intra-BLA infusion of lentivirus-expressing Akap5 short hairpin RNA or Ht-31 prevented depressive-like behaviors and normalized phosphorylation of serine 845 and surface expression of AMPAR subunit 1 (GluA1) in the BLA of CRS mice. Finally, blockage of AKAP150-PKA complex signaling rescued the changes in AMPAR-mediated miniature excitatory postsynaptic currents in depressive-like mice. CONCLUSIONS: These results suggest that AKAP150-PKA directly modulates BLA neuronal synaptic strength, and that AKAP150-PKA-GluA1 streamline signaling complex is responsible for CRS-induced disruption of synaptic AMPAR-mediated transmission and depressive-like behaviors in mice.
BACKGROUND: The basolateral amygdala (BLA) has been widely implicated in the pathophysiology of major depressive disorder. A-kinase anchoring protein 150 (AKAP150) directs kinases and phosphatases to synaptic glutamate receptors, controlling synaptic transmission and plasticity. However, the role of the AKAP150 in the BLA in major depressive disorder remains poorly understood. METHODS:Depressive-like behaviors in C57BL/6J mice were developed by chronic restraint stress (CRS). Mice received either intra-BLA injection of lentivirus-expressing Akap5 short hairpin RNA or Ht-31, a peptide to disrupt the interaction of AKAP150 and protein kinase A (PKA), followed by depressive-like behavioral tests. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptor (AMPAR)-mediated miniature excitatory postsynaptic currents were recorded by whole-cell patch-clamp techniques. RESULTS: Chronic stress exposure induced depressive-like behaviors, which were accompanied by an increase in total and synaptic AKAP150 expression in the BLA. Accordingly, CRS facilitated the association of AKAP150 with PKA, but not of calcineurin in the BLA. Intra-BLA infusion of lentivirus-expressing Akap5 short hairpin RNA or Ht-31 prevented depressive-like behaviors and normalized phosphorylation of serine 845 and surface expression of AMPAR subunit 1 (GluA1) in the BLA of CRSmice. Finally, blockage of AKAP150-PKA complex signaling rescued the changes in AMPAR-mediated miniature excitatory postsynaptic currents in depressive-like mice. CONCLUSIONS: These results suggest that AKAP150-PKA directly modulates BLA neuronal synaptic strength, and that AKAP150-PKA-GluA1 streamline signaling complex is responsible for CRS-induced disruption of synaptic AMPAR-mediated transmission and depressive-like behaviors in mice.