title: The rapid antidepressant and anxiolytic-like effects of YY-21 involve enhancement of excitatory synaptic transmission via activation of mTOR signaling in the mPFC.
abstract: Although antidepressants have been widely prescribed to treat patients with major depressive disease (MDD), there is little disagreement over the need for improved antidepressant therapeutics as the typical treatments have a slow therapeutic onset and moderate efficacy. In the present study, we assessed a novel compound, YY-21, from timosaponin B-III derived from sarsasapogenin of Anemarrhenae Rhizoma. From the initial results, we found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10min as determined by excitatory postsynaptic current (EPSC) and field excitatory postsynaptic potential (fEPSP) in medial prefrontal cortex (mPFC) slices, respectively. YY-21 demonstrated anxiolytic-like effects following acute administration in naïve animals and reversed the depressive-like and anxiety phenotypes induced by chronic unpredictable mild stress (CMS) with a relatively fast therapeutic onset. Furthermore, analysis of intracellular signaling pathways showed that YY-21 normalized the CMS-induced low protein levels of GluN2B, p-mTOR, synaptic-related proteins, such as BDNF, PSD-95 and GluA1. Pre-application of the mTOR-selective inhibitor rapamycin blocked YY-21-induced long-term synaptic enhancement. These findings suggest that the activation of BDNF-dependent mTOR signaling, which produces a rapid increase in the postsynaptic protein PSD-95 and GluA1 and further triggers the long-term enhancement of synaptic neurotransmission, may be the mechanism underlying the rapid antidepressant and anxiolytic effects induced by YY-21.
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: guofei@simm.ac.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Guo
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
authors.forename: Fuyi
authors.initials: F
authors.lastname: Shen
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: cghuang@simm.ac.cn.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Huang
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: liyang@simm.ac.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000737:chemistry / Q000494:pharmacology*; D013315:Stress, Psychological; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D012503:Saponins; C000626015:YY-21 saponin; D018698:Glutamic Acid; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: Synaptic proteins; Synaptic transmission; YY-21; mTOR