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

doi:10.1016/j.ynstr.2020.100240

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

Neurobiol Stress. 2020 Jul 13:13:100240. doi: 10.1016/j.ynstr.2020.100240. eCollection 2020 Nov.

Authors

Affiliations

¹ Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA.
² Department of Psychology, College of Arts and Sciences, The Ohio State University, Columbus, OH, USA.
³ Department of Biomedical Sciences, University of Cagliari, Italy.
⁴ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.

Abstract

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.

Keywords: BBB, Blood brain barrier; CA, Cornu ammonis; DCX, Doublecortin; DEET, N, N-Diethyl-meta-toluamide; DG, Dentate gyrus; EAAT2, Excitatory amino acid transporter 2; GABA, γ-aminobutyric acid; GFAP, glial fibrillary acidic protein; GWI, gulf war illness; Gulf war illness; LTP, Long term potentiation; Mood deficits and cognitive impairments; PB, Pyridostigmine bromide; PSD95, Postsynaptic density protein 95; PV, Parvalbumin; TBS, Theta burst stimulation; Therapy; Traumatic stress; Tripartite glutamatergic synapses; fEPSP, field excitatory postsynaptic potentials; sEPSC/mEPSC, Spontaneous/miniature excitatory postsynaptic current; sIPSC/mIPSC, Spontaneous/miniature inhibitory postsynaptic current; vGAT, Vesicular inhibitory amino acid transporter; vGLUT1, Vesicular glutamate transporter 1.

Abstract

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