PMID- 29421611 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20191126 IS - 1095-9564 (Electronic) IS - 1074-7427 (Linking) VI - 149 DP - 2018 Mar TI - GPR30 activation improves memory and facilitates DHPG-induced LTD in the hippocampal CA3 of middle-aged mice. PG - 10-19 LID - S1074-7427(18)30017-0 [pii] LID - 10.1016/j.nlm.2018.02.005 [doi] AB - Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle-aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15. Interestingly, a group I metabotropic glutamate receptor (mGluR) agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD) in mossy fiber-cornu ammonis 3 (MF-CA3) synapses but not Schaffer collateral-CA1 (SC-CA1) synapses was facilitated in brain slices from G1-treated middle-aged mice. Long-term potentiation (LTP) in SC-CA1 synapses was not affected in slices from G1-treated mice. The effects of GPR30 activation on memory and DHPG-LTD in MF-CA3 synapses were further confirmed by viral expression of GPR30 in the CA3. The regulation of hippocampal synaptic plasticity by G1 treatment might be related to brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling, as G15 also blocked G1-induced activation of the BDNF-TrkB pathway. Moreover, we found that DHPG triggered GluA internalization in slices from G1-treated mice but not control mice. Pharmacological experiments showed that G1-mediated facilitation of DHPG-induced LTD in MF-CA3 synapses was dependent on protein kinase B (Akt), mammalian target of rapamycin (mTor), and TrkB signaling. In conclusion, our results indicate that GPR30 activation improves memory in middle-aged mice, likely through facilitating synaptic plasticity in the CA3. This study provides novel evidence that GPR30 activation can improve memory in middle-aged animals. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Xu, Wen AU - Xu W AD - Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Anhui Provincial Hospital, Hefei 230001, China. FAU - Cao, Jian AU - Cao J AD - Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China. FAU - Zhou, Yan AU - Zhou Y AD - Department of Children's Health Prevention, Anhui Provincial Children's Hospital, Hefei 230029, China. FAU - Wang, Lina AU - Wang L AD - Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China. FAU - Zhu, Guoqi AU - Zhu G AD - Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China. Electronic address: guoqizhu@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180206 PL - United States TA - Neurobiol Learn Mem JT - Neurobiology of learning and memory JID - 9508166 RN - 0 (4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline) RN - 0 (Benzodioxoles) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Excitatory Amino Acid Agonists) RN - 0 (GPER1 protein, mouse) RN - 0 (Membrane Glycoproteins) RN - 0 (Quinolines) RN - 0 (Receptors, Estrogen) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Receptors, Metabotropic Glutamate) RN - 0 (metabotropic glutamate receptor type 1) RN - 534-82-7 (Methoxyhydroxyphenylglycol) RN - EC 2.7.10.1 (Ntrk2 protein, mouse) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - UEH9K539KJ (3,4-dihydroxyphenylglycol) SB - IM MH - Age Factors MH - Animals MH - Benzodioxoles/pharmacology MH - Brain-Derived Neurotrophic Factor/metabolism MH - CA3 Region, Hippocampal/*drug effects/metabolism MH - Excitatory Amino Acid Agonists/*pharmacology MH - Fear/drug effects MH - Female MH - Long-Term Synaptic Depression/*drug effects MH - Male MH - Membrane Glycoproteins/metabolism MH - Methoxyhydroxyphenylglycol/*analogs & derivatives/pharmacology MH - Mice MH - Neuronal Plasticity/drug effects MH - Protein-Tyrosine Kinases/metabolism MH - Quinolines/pharmacology MH - Receptors, Estrogen/*antagonists & inhibitors/metabolism MH - Receptors, G-Protein-Coupled/*antagonists & inhibitors/metabolism MH - Receptors, Metabotropic Glutamate/agonists MH - Signal Transduction/drug effects MH - Spatial Memory/drug effects MH - Synapses/drug effects/metabolism OTO - NOTNLM OT - Aging OT - BDNF OT - GPR30 OT - Long-term depression OT - Memory deficit EDAT- 2018/02/09 06:00 MHDA- 2019/09/17 06:00 CRDT- 2018/02/09 06:00 PHST- 2017/11/21 00:00 [received] PHST- 2018/01/05 00:00 [revised] PHST- 2018/02/04 00:00 [accepted] PHST- 2018/02/09 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/02/09 06:00 [entrez] AID - S1074-7427(18)30017-0 [pii] AID - 10.1016/j.nlm.2018.02.005 [doi] PST - ppublish SO - Neurobiol Learn Mem. 2018 Mar;149:10-19. doi: 10.1016/j.nlm.2018.02.005. Epub 2018 Feb 6.