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Synaptic mechanisms underlying the rapid‐acting antidepressant actions of ketamine
Author(s) -
Zobel Allison,
Pope Brock,
Rehman Zarin,
Herring Laura,
Wauson Eric,
Graves Lee,
Duric Vanja,
Yuan LiLian
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb612
Subject(s) - cofilin , synaptogenesis , pi3k/akt/mtor pathway , neuroscience , microbiology and biotechnology , nmda receptor , chemistry , antidepressant , actin cytoskeleton , biology , signal transduction , hippocampus , cytoskeleton , receptor , cell , biochemistry
Ketamine at sub‐anesthetic doses has shown promising results as a potent and fast‐acting antidepressant. Evidence from animal model studies suggests that the functional restoration by ketamine is associated with activation of MAPK and mTOR signaling cascades in the prefrontal cortex (PFC) within a few hours of ketamine administration, followed by a second wave of synaptic protein upregulation. Together, these molecular events lead to rapid synaptogenesis and reversal of neural atrophy. Furthermore, (2 R , 6 R )‐hydroxynorketamine (HNK) has recently been identified as the main active component of ketamine metabolism. HNK is believed to be responsible for the antidepressant actions of ketamine, but with minimal side effects, and potentially through NMDAR‐independent mechanism of action. However, critical gaps exist in understanding the exact molecular mechanisms of ketamine actions. Thus, it would be of great importance and interest to delineate the molecular mechanisms that translate mTOR activation into synaptogenesis‐based structural remodeling. Cofilin and its upstream pathways, ideally positioned to bridge the gap between mTOR activation and spine formation, have emerged from an unbiased kinome/phosphoproteome screening for targets of ketamine treatment. As the major cytoskeletal component of dendritic spines, actin controls spine morphology and formation through changes in its polymerization state. Actin polymerization is negatively regulated by activation of cofilin protein. Phospho‐antibody based assays and direct or indirect measurement of kinase activity are currently underway to validate those targets in acutely and chronically stressed animal models. We anticipate addressing the significance of cofilin phosphorylation and actin polymerization in antidepressant responses of ketamine and HNK, and whether those responses are modulated by other factors including stress and sex. Support or Funding Information NIH grant MH108043 and IOER funds This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .