PMID- 30143658 OWN - NLM STAT- MEDLINE DCOM- 20191030 LR - 20191030 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 8 IP - 1 DP - 2018 Aug 24 TI - PSD-95-nNOS Coupling Regulates Contextual Fear Extinction in the Dorsal CA3. PG - 12775 LID - 10.1038/s41598-018-30899-4 [doi] LID - 12775 AB - Fear extinction depends on N-methyl-D-aspartate glutamate receptors (NMDARs) and brain-derived neurotrophic factor (BDNF) activation in the limbic system. However, postsynaptic density-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) coupling, the downstream signaling of NMDARs activation, obstructs the BDNF signaling transduction. Thus, we wondered distinct roles of NMDAR activation and PSD-95-nNOS coupling on fear extinction. To explore the mechanisms, we detected protein-protein interaction using coimmunoprecipitation and measured protein expression by western blot. Contextual fear extinction induced a shift from PSD-95-nNOS to PSD-95-TrkB association in the dorsal hippocampus and c-Fos expression in the dorsal CA3. Disrupting PSD-95-nNOS coupling in the dorsal CA3 up-regulated phosphorylation of extracellular signal-regulates kinase (ERK) and BDNF, enhanced the association of BDNF-TrkB signaling with PSD-95, and promoted contextual fear extinction. Conversely, blocking NMDARs in the dorsal CA3 down-regulated BDNF expression and hindered contextual fear extinction. NMDARs activation and PSD-95-nNOS coupling play different roles in modulating contextual fear extinction in the hippocampus. Because inhibitors of PSD-95-nNOS interaction produce antidepressant and anxiolytic effect without NMDAR-induced side effects, PSD-95-nNOS could be a valuable target for PTSD treatment. FAU - Cai, Cheng-Yun AU - Cai CY AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Chen, Chen AU - Chen C AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Zhou, Ying AU - Zhou Y AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Han, Zhou AU - Han Z AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Qin, Cheng AU - Qin C AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Cao, Bo AU - Cao B AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Tao, Yan AU - Tao Y AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Bian, Xin-Lan AU - Bian XL AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Lin, Yu-Hui AU - Lin YH AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Chang, Lei AU - Chang L AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Wu, Hai-Yin AU - Wu HY AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Luo, Chun-Xia AU - Luo CX AUID- ORCID: 0000-0002-9840-0402 AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. FAU - Zhu, Dong-Ya AU - Zhu DY AD - Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing, 211166, People's Republic of China. dyzhu@njmu.edu.cn. AD - Departments of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People's Republic of China. dyzhu@njmu.edu.cn. AD - The key laboratory of human functional genomics of Jiangsu Province, Nanjing, 211166, People's Republic of China. dyzhu@njmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180824 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Dlg4 protein, mouse) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type I) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - CA3 Region, Hippocampal/*physiology MH - Disks Large Homolog 4 Protein/*metabolism MH - Extinction, Psychological/*physiology MH - Fear/*physiology MH - Male MH - Mice, Inbred C57BL MH - Models, Biological MH - Nitric Oxide Synthase Type I/*metabolism MH - Receptor, trkB/metabolism MH - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism MH - Signal Transduction PMC - PMC6109109 COIS- The authors declare no competing interests. EDAT- 2018/08/26 06:00 MHDA- 2019/10/31 06:00 PMCR- 2018/08/24 CRDT- 2018/08/26 06:00 PHST- 2017/05/22 00:00 [received] PHST- 2018/04/17 00:00 [accepted] PHST- 2018/08/26 06:00 [entrez] PHST- 2018/08/26 06:00 [pubmed] PHST- 2019/10/31 06:00 [medline] PHST- 2018/08/24 00:00 [pmc-release] AID - 10.1038/s41598-018-30899-4 [pii] AID - 30899 [pii] AID - 10.1038/s41598-018-30899-4 [doi] PST - epublish SO - Sci Rep. 2018 Aug 24;8(1):12775. doi: 10.1038/s41598-018-30899-4.