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

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

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

Author(s) -

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,

Chienliang Glenn Lin

Publication year - 2020

Publication title -

neurobiology of stress

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.481

H-Index - 33

ISSN - 2352-2895

DOI - 10.1016/j.ynstr.2020.100240

Subject(s) - glutamatergic , neuroscience , mood , glutamate receptor , neurogenesis , hippocampal formation , cognitive decline , cognition , psychology , medicine , disease , psychiatry , dementia , receptor

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.

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