title: The antidepressant-like effect of alarin is related to TrkB-mTOR signaling and synaptic plasticity.
abstract: Alarin is a newly derived neuropeptide from a splice variant of the galanin-like peptide gene. We previously showed that alarin has an antidepressant-like effect by increasing the activity of the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) pathways, mediated by the tropomyosin-related kinase B receptor in the unpredictable chronic mild stress (UCMS) mouse model. Administration of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, prevents the rapid antidepressant-like effect induced by ketamine in animal models, indicating a vital role of mTOR in depression pathophysiology. mTOR is a target of the ERK and AKT pathways that regulates the initiation of protein translation via its downstream components: ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). Therefore, we hypothesized that the antidepressant-like effects of alarin were achieved by activating ERK/AKT pathways, increasing the activity of mTOR and its downstream signaling components that contribute to protein synthesis required for synaptic plasticity. Our results suggest that intracerebroventricular administration of alarin significantly ameliorates depression-like behaviors in the UCMS mouse model. Furthermore, alarin restored UCMS-induced reductions of p70S6K and post-synaptic density 95 (PSD-95) mRNA levels, and of phospho-mTOR and phospho-4EBP1 in the prefrontal cortex, hippocampus, hypothalamus, and olfactory bulb. Additionally, alarin reversed the UCMS-induced downregulation of PSD-95 and synapsin I protein expression in these brain regions. Thus, the antidepressant-like effects of alarin may be mediated by restoring decreased activity of the mTOR signaling pathway and expression of synaptic proteins. Our findings help advance the understanding of depression pathophysiology.
authors.affiliation: Department of Pharmacy, The First People's Hospital of Wujiang, Suzhou 215200, China.
authors.forename: Fuzhi
authors.initials: F
authors.lastname: Zhuang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical University, Xuzhou 221004, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical University, Xuzhou 221004, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical University, Xuzhou 221004, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, The People's Hospital of Jiangyin, Wuxi 214400, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical University, Xuzhou 221004, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical University, Xuzhou 221004, China.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical University, Xuzhou 221004, China. Electronic address: gushling@aliyun.com.
authors.forename: Shuling
authors.initials: S
authors.lastname: Gu
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D003863:Depression / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism; D044089:Galanin-Like Peptide / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000150:complications; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D044089:Galanin-Like Peptide; D012333:RNA, Messenger; C581934:alarin; C546843:mTOR protein, mouse; D020813:Receptor, trkB; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Alarin; Depression; Synaptic plasticity; mTOR; p70S6K