Corticosteroid-induced dendrite loss and behavioral deficiencies can be blocked by activation of Abl2/Arg kinase

• Type of Material: Article
• Authors: Lauren P. Shapiro, Emory School of Medicine; Mitchell H. Omar, Yale University; Anthony J. Koleske, Yale University; Shannon L Gourley, Emory University
• Language: English
• Date: 2017-12-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.mcn.2017.10.007
• Title of Journal or Parent Work: Molecular and Cellular Neuroscience
• ISSN: 1044-7431
• Volume: 85
• Start Page: 226
• End Page: 234
• Grant/Funding Information: This work was supported by PHS grants NS089662 and NS089439 (AJK) and MH101477 (SLG); Children's Healthcare of Atlanta (SLG); and training grants F31NS090767, T32NS007224, F31MH109208, and T32GM008602.; The components of this project performed at the Yerkes National Primate Research Center were also supported by the Office of Research Infrastructure Programs/OD P51OD011132.
• Keywords: BRAIN; STABILITY; Neurosciences & Neurology; AMYGDALA; VOLUME; Life Sciences & Biomedicine; PREFRONTAL CORTEX; Neurosciences; DEPRESSION; FAMILY KINASES; Science & Technology; CHRONIC STRESS; HIPPOCAMPUS; SYNAPSES
• Research Categories: Biology, Molecular; Biology, Neuroscience; Health Sciences, Pharmacology

Abstract

Stressor exposure induces neuronal remodeling in specific brain regions. Given the persistence of stress-related illnesses, key next steps in determining the contributions of neural structure to mental health are to identify cell types that fail to recover from stressor exposure and to identify “trigger points” and molecular underpinnings of stress-related neural degeneration. We evaluated dendrite arbor structure on hippocampal CA1 pyramidal neurons before, during, and following prolonged exposure to one key mediator of the stress response – corticosterone (cortisol in humans). Basal dendrite arbors progressively simplified during a 3-week exposure period, and failed to recover when corticosterone was withdrawn. Corticosterone exposure decreased levels of the dendrite stabilization factor Abl2/Arg nonreceptor tyrosine kinase and phosphorylation of its substrates p190RhoGAP and cortactin within 11 days, suggesting that disruption of Arg-mediated signaling may trigger dendrite arbor atrophy and, potentially, behavioral abnormalities resulting from corticosterone exposure. To test this, we administered the novel, bioactive Arg kinase activator, 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin, 5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2,4-imidazolidinedione (DPH), in conjunction with corticosterone. We found that repeated treatment corrected CA1 arbor structure, otherwise simplified by corticosterone. DPH also corrected corticosterone-induced errors in a hippocampal-dependent reversal learning task and anhedonic-like behavior. Thus, pharmacological compounds that target cytoskeletal regulators, rather than classical neurotransmitter systems, may interfere with stress-associated cognitive decline and mental health concerns.