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

• Published in: Neurobiology of stress Vol. 13; p. 100240
• Main Authors: Wang, Xueqin, Xu, Zan, Zhao, Fangli, Lin, Kuanhung J., Foster, Joshua B., Xiao, Tianqi, Kung, Nydia, Askwith, Candice C., Bruno, John P., Valentini, Valentina, Hodgetts, Kevin J., Lin, Chien-liang Glenn
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2020; Elsevier
• Subjects: Gulf war illness; Mood deficits and cognitive impairments; Original; Therapy; Traumatic stress; Tripartite glutamatergic synapses; Mood deficits and cognitive impairments; Therapy; BBB; DG; TBS; PV; sEPSC/mEPSC; Gulf war illness; EAAT2; LTP; Tripartite glutamatergic synapses; DEET; GFAP; PB; vGAT; fEPSP; PSD95; sIPSC/mIPSC; DCX; GABA; GWI; Traumatic stress; CA; vGLUT1; GFAP, glial fibrillary acidic protein; LTP, Long term potentiation; PV, Parvalbumin; sEPSC/mEPSC, Spontaneous/miniature excitatory postsynaptic current; CA, Cornu ammonis; GABA, γ-aminobutyric acid; BBB, Blood brain barrier; DG, Dentate gyrus; DEET, N, N-Diethyl-meta-toluamide; EAAT2, Excitatory amino acid transporter 2; PSD95, Postsynaptic density protein 95; vGAT, Vesicular inhibitory amino acid transporter; TBS, Theta burst stimulation; fEPSP, field excitatory postsynaptic potentials; sIPSC/mIPSC, Spontaneous/miniature inhibitory postsynaptic current; DCX, Doublecortin; PB, Pyridostigmine bromide; GWI, gulf war illness; vGLUT1, Vesicular glutamate transporter 1
• ISSN: 2352-2895; 2352-2895
• DOI: 10.1016/j.ynstr.2020.100240

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.
•Exposure to Gulf War-related agents and stress causes long-term hippocampal glutamatergic synapses impairment.•LDN/OSU-215111, a small-molecule that enhances tripartite synapses, normalizes hippocampal deficits in a mouse model of GWI.•LDN/OSU-215111 effectively ameliorates mood deficits, cognitive impairments, and fatigue in a mouse model of GWI.