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P4‐221: GABA‐linked acceleration of aging‐associated memory decline in APP/PS1 transgenic mouse and its pharmacological treatment by picrotoxin
Author(s) -
Yoshiike Yuji,
Kimura Tetsuya,
Yamashita Shunji,
Furudate Hiroyuki,
Mizoroki Tatsuya,
Murayama Miyuki,
Takashima Akihiko
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.2289
Subject(s) - bicuculline , long term potentiation , gabaa receptor , neuroscience , excitatory postsynaptic potential , picrotoxin , hippocampal formation , genetically modified mouse , hippocampus , synaptic plasticity , downregulation and upregulation , transgene , chemistry , endocrinology , psychology , biology , medicine , inhibitory postsynaptic potential , receptor , biochemistry , gene
gonadotropin-releasing hormone 1 (GnRH1) by producing luteinizing hormone (LH) that in turn induces neurosteroid synthesis. Methods: To test whether there may be an autocrine/paracrine feedback mechanism within the brain that modulates neurosteroid synthesis, as is the case for the regulation of gonadal sex steroid production by the HPG axis, 3-month old female BALB/c mice were either left intact, ovariectomized (OVX) or OVX and treated with a cholesterol (control), E2, P4 or E2 P4 pellet for 3 d. Results: Ovariectomy, which induces a dramatic increase in GnRH and gonadotropin synthesis, decreased the expression of GnRH receptor 1 (GnRHR1) and LH variants but did not alter estrogen receptor (ER ) expression. Ovariectomy had a differential affect on steroidogenic acute regulatory protein (StAR) expression, increasing the 30and 32-kDa StAR variants. Treatment of OVX animals with E2, P4 or E2 P4 all potently suppressed the expression of brain LH , GnRHR1 and ER , but increased the 37-kDa StAR variant. Conclusions: These results indicate that negative feedback loop(s) exist within the brain to regulate GnRH and LH signaling, and neurosteroid production via the regulation of StAR expression. Thus, circulating sex steroids can regulate the expression of components of the neurosteroid synthesis pathway in the brain, and may therefore play a major role in the regulation of neurosteroid synthesis. Given the importance of sex steroids to brain function, it is possible that autocrine/paracrine neurosteroid production may be a mechanism to fine-tune the level of sex steroids in the brain. Understanding the feedback loops in the brain that regulate neurosteroid production has important implications for developing therapeutic strategies to maintain brain sex steroid levels and cognition.