Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Aging (Albany NY). 2020 Nov 16;12(22):23146-23164. doi: 10.18632/aging.104080.
Although more patients survive sepsis and are increasingly discharged from the hospital, they often experience long-term cognitive and psychological impairment with significant socioeconomic impact. However, the pathophysiological mechanisms have not been fully elucidated. In the present study, we showed that LPS induced long-term neurobehavioral abnormities, as reflected by significantly decreased freezing time to context and sucrose preference. Using a high-throughput quantitative proteomic screen, we showed that phosphorylation of synaptic GTPase-activating protein 1 (pSynGAP1) was identified as the hub of synaptic plasticity and was significantly decreased following LPS exposure. This decreased pSynGAP was associated with significantly lower theta and gamma oscillations in the CA1 of the hippocampus. Notably, restoration of pSynGAP1 by roscovitine was able to reverse most of these abnormities. Taken together, our study suggested that pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might play a critical role in long-term neurobehavioral abnormities of sepsis survivors.
尽管越来越多的脓毒症患者存活下来并出院，但他们经常经历长期的认知和心理障碍，对社会经济产生重大影响。然而，其病理生理机制尚未完全阐明。在本研究中，我们发现 LPS 诱导了长期的神经行为异常，表现为对上下文的冻结时间显著减少和蔗糖偏好降低。使用高通量定量蛋白质组学筛选，我们发现突触 GTP 酶激活蛋白 1（pSynGAP1）的磷酸化被鉴定为突触可塑性的枢纽，并且在 LPS 暴露后显著降低。这种降低的 pSynGAP1 与海马 CA1 中θ和γ振荡明显降低有关。值得注意的是，罗司卡维汀恢复 pSynGAP1 能够逆转大多数这些异常。综上所述，我们的研究表明，pSynGAP1 干扰介导的海马振荡网络损伤可能在脓毒症幸存者的长期神经行为异常中发挥关键作用。
