title: Letrozole regulates actin cytoskeleton polymerization dynamics in a SRC-1 dependent manner in the hippocampus of mice.
abstract: In the hippocampus, local estrogens (E2) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E2and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics. Then we used aromatase inhibitor letrozole (LET) to block local E2synthesis and examined the changes of these proteins and steroid receptor coactivator-1 (SRC-1), the predominant coactivator for steroid nuclear receptors. Finally, SRC-1 specific RNA interference was used to examine the effects of SRC-1 on the expression of these actin remodeling proteins. The results showed a V-type profile for aromatase and increased profiles for actin cytoskeleton proteins in both male and female hippocampus without obvious sex differences. LET treatment dramatically decreased the F-actin/G-actin ratio, the expression of Rictor, phospho-AKT (ser473), Profilin-1, phospho-Cofilin (Ser3), and SRC-1 in a dose-dependent manner. In vitro studies demonstrated that LET induced downregulation of these proteins could be reversed by E2, and E2induced increase of these proteins were significantly suppressed by SRC-1 shRNA interference. These results for the first time clearly demonstrated that local E2inhibition could induce aberrant actin polymerization; they also showed an important role of SRC-1 in the mediation of local E2action on hippocampal synaptic plasticity by regulation of actin cytoskeleton dynamics.
authors.affiliation: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yangang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Student Brigade, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Nursing, Third Military Medical University, Chongqing 400038, China.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.affiliation: School of Nursing, Third Military Medical University, Chongqing 400038, China; Department of Nursing, Sichuan Nursing Vocational College, Chengdu 610100, China.
authors.forename: Linli
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Jikai
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China. Electronic address: zhangjqtmmu@yahoo.com.
authors.forename: Jiqiang
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000737:chemistry; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism*; D015536:Down-Regulation; D004967:Estrogens / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology*; D000077289:Letrozole; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000737:chemistry*; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000199:Actins; D047072:Aromatase Inhibitors; D004967:Estrogens; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1
keywords: Actin cytoskeleton; Aromatase; Estrogens; Hippocampus; Letrozole; Steroid receptor coactivator-1