Restoring tripartite glutamatergic synapses: A potential therapy for mood and cognitive deficits in Gulf War illness

Xueqin Wang; Zan Xu; Fangli Zhao; Kuanhung J. Lin; Joshua B. Foster; Tianqi Xiao; Nydia Kung; Candice C. Askwith; John P. Bruno; Valentina Valentini; Kevin J. Hodgetts; Chien-liang Glenn Lin

Neurobiology of Stress (Nov 2020)

Restoring tripartite glutamatergic synapses: A potential therapy for mood and cognitive deficits in Gulf War illness

Xueqin Wang,
Zan Xu,
Fangli Zhao,
Kuanhung J. Lin,
Joshua B. Foster,
Tianqi Xiao,
Nydia Kung,
Candice C. Askwith,
John P. Bruno,
Valentina Valentini,
Kevin J. Hodgetts,
Chien-liang Glenn Lin

Affiliations

Xueqin Wang: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
Zan Xu: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
Fangli Zhao: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
Kuanhung J. Lin: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
Joshua B. Foster: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
Tianqi Xiao: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
Nydia Kung: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
Candice C. Askwith: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
John P. Bruno: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA; Department of Psychology, College of Arts and Sciences, The Ohio State University, Columbus, OH, USA
Valentina Valentini: Department of Psychology, College of Arts and Sciences, The Ohio State University, Columbus, OH, USA; Department of Biomedical Sciences, University of Cagliari, Italy
Kevin J. Hodgetts: Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA
Chien-liang Glenn Lin: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA; Corresponding author. Graves Hall 4066D, 333 W. 10th Ave, Columbus, OH, 43210, USA.

Journal volume & issue: Vol. 13
p. 100240

Abstract

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Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the pathophysiology remains elusive. Neurological problems are among the most commonly reported symptoms. In this study, we investigated the glutamatergic system in the hippocampi of mice exposed to war-related chemical agents and stress. Mice developed Gulf War illness-like symptoms, including mood deficits, cognitive impairments, and fatigue. They exhibited the following pathological changes in hippocampi: elevated extracellular glutamate levels, impaired glutamatergic synapses, astrocyte atrophy, loss of interneurons, and decreased neurogenesis. LDN/OSU-215111 is a small-molecule that can strengthen the structure and function of both the astrocytic processes and the glutamatergic synapses that together form the tripartite synapses. We found that LDN/OSU-215111 effectively prevented the development of mood and cognitive deficits in mice when treatment was implemented immediately following the exposure. Moreover, when symptoms were already present, LDN/OSU-215111 still significantly ameliorated these deficits; impressively, benefits were sustained one month after treatment cessation, indicating disease modification. LDN/OSU-215111 effectively normalized hippocampal pathological changes. Overall, this study provides strong evidence that restoration of tripartite glutamatergic synapses by LDN/OSU-215111 is a potential therapy for Gulf War illness.

Published in Neurobiology of Stress

ISSN: 2352-2895 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry: Neurology. Diseases of the nervous system; Science: Physiology: Neurophysiology and neuropsychology
Website: http://www.journals.elsevier.com/neurobiology-of-stress/

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