title: Steroid receptor coactivator-1 mediates letrozole induced downregulation of postsynaptic protein PSD-95 in the hippocampus of adult female rats.
abstract: Hippocampus local estrogen which is converted from androgen that catalyzed by aromatase has been shown to play important roles in the regulation of learning and memory as well as cognition through action on synaptic plasticity, but the underlying mechanisms are poorly understood. Steroid receptor coactivator-1 (SRC-1) is one of the coactivators of steroid nuclear receptors; it is widely distributed in brain areas that related to learning and memory, reproductive regulation, sensory and motor information integration. Previous studies have revealed high levels of SRC-1 immunoreactivities in the hippocampus; it is closely related to the levels of synaptic proteins such as PSD-95 under normal development or gonadectomy, but its exact roles in the regulation of these proteins remains unclear. In this study, we used aromatase inhibitor letrozole in vivo and SRC-1 RNA interference in vitro to investigate whether SRC-1 mediated endogenous estrogen regulation of hippocampal PSD-95. The results revealed that letrozole injection synchronously decreased hippocampal SRC-1 and PSD-95 in a dose-dependant manner. Furthermore, when SRC-1 specific shRNA pool was applied to block the expression of SRC-1 in the primary hippocampal neuron culture, both immunocytochemistry and Western blot revealed that levels of PSD-95 were also decreased significantly. Taking together, these results provided the first evidence that SRC-1 mediated endogenous estrogen regulation of hippocampal synaptic plasticity by targeting the expression of synaptic protein PSD-95. Additionally, since letrozole is frequently used to treat estrogen-sensitive breast cancer, the above results also indicate its potential side effects in clinical administration.
authors.affiliation: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China; Cadet Brigade, 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; Cadet Brigade, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Huangfu
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: Department of Neurobiology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China; Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. Electronic address: 574235375@qq.com.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
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: D000818:Animals; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000077289:Letrozole; D008565:Membrane Proteins / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D056920:Nuclear Receptor Coactivator 1
keywords: Aromatase; Estrogens; Hippocampus; Steroid receptor coactivator-1; Synaptic plasticity