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PSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

ABSTRACT: 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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7746391 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

Wang Yong Y Wei Hua H Tong Jianhua J Ji Muhuo M Yang Jianjun J

Aging 20201116 22

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 sc ...[more]

PMID: 33203791

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Project description:Sepsis is the most common cause of hospitalization worldwide. Millions of people survive sepsis each year and are at risk for rehospitalization and death. Pulmonary complications such as respiratory failure due to pneumonia and exacerbation of chronic respiratory disease are among the most common reasons for rehospitalization in sepsis survivors. In order to prevent additional morbidity and death in patients surviving sepsis, we must establish biomarkers to identify patients at risk for pulmonary complications and develop treatments. Late complications in sepsis survivors, particularly nosocomial infections, are proposed to occur through persistent immune reprogramming after sepsis known as immunoparalysis. However, pro-inflammatory immune reprogramming in the form of primed or enhanced responses to secondary stimuli has also been described and could directly contribute to tissue injury and death. Primed immune responses and their contribution to long-term sepsis complications remains understudied. We hypothesize that primed immune responses to inflammatory stimuli in the lung after sepsis are associated with pulmonary complications in survivors of sepsis. To this end, we developed a model of antibiotic treated sepsis induced by cecal ligation and puncture followed three weeks later by secondary challenge with intranasal lipopolysaccharide to induce inflammatory lung injury. We find that mice surviving sepsis have enhanced lung injury responses in the setting of an exaggerated proinflammatory immune response, including primed Ly6Chi monocyte Tnf expression. Using RNA sequencing, we identified derangements in lung gene expression after CLP prior to LPS administration which may mediate enhanced lung injury in this model. One potential mediator, S100A8/A9, was also found to be elevated in the circulation of human sepsis survivors for up to 180 days after sepsis. These findings validate our model and identify S100A8/A9 as one of many potential biomarkers and therapeutic targets for patients at risk for long-term pulmonary complications after sepsis. The role of S100A8/A9, monocyte priming, and other factors predisposing to enhanced lung injury responses and pulmonary complications after sepsis warrant further investigation in humans and mice.

Dataset Information

PSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

Publications

pSynGAP1 disturbance-mediated hippocampal oscillation network impairment might contribute to long-term neurobehavioral abnormities in sepsis survivors.

Similar Datasets

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