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.

海湾战争疾病与接触战争相关化学制剂和创伤性应激有关。目前，尚无有效的治疗方法，其病理生理学仍然难以捉摸。神经系统问题是最常见的症状之一。在这项研究中，我们研究了暴露于战争相关化学制剂和压力的小鼠海马体中的谷氨酸能系统。小鼠出现了类似海湾战争疾病的症状，包括情绪缺陷、认知障碍和疲劳。他们的海马体表现出以下病理变化：细胞外谷氨酸水平升高、谷氨酸能突触受损、星形胶质细胞萎缩、中间神经元丧失和神经发生减少。 LDN/OSU-215111 是一种小分子，可以增强星形胶质细胞过程和共同形成三联突触的谷氨酸突触的结构和功能。我们发现，在接触 LDN/OSU-215111 后立即进行治疗，可以有效防止小鼠情绪和认知缺陷的发展。此外，当症状已经存在时，LDN/OSU-215111 仍然显着改善这些缺陷；令人印象深刻的是，治疗停止后一个月仍持续获益，表明疾病得到改善。 LDN/OSU-215111 有效地使海马病理变化正常化。总体而言，这项研究提供了强有力的证据，表明 LDN/OSU-215111 恢复三联谷氨酸突触是海湾战争疾病的潜在疗法。