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Neuroinflammation-Induced Downregulation of Hippocampacal Neuregulin 1-ErbB4 Signaling in the Parvalbumin Interneurons Might Contribute to Cognitive Impairment in a Mouse Model of Sepsis-Associated Encephalopathy

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Abstract

Sepsis-associated encephalopathy (SAE) is a common complication associated with poor prognosis in septic patients, but the underlying mechanism remains unclear. We hypothesized that disturbed neuregulin 1 (NRG1)-ErbB4 signaling in the parvalbumin interneurons was involved in sepsis-induced cognitive impairment in a mouse model of SAE. The SAE model was induced by cecal ligation/perforation (CLP). Animals were randomly divided into the following six groups: sham + vehicle group, sham + NRG1 group, CLP + vehicle group, CLP + NRG1 group, CLP + NRG1 + AG1478 (ErbB4 inhibitor) group, and CLP + minocycline group. Behavioral tests and in vivo electrophysiology were performed at the indicated time points. The brain tissues were harvested to determine the levels of hippocampcal cytokines, IBA1-positive cells, NRG1, ErbB4, and parvalbumin. In the present study, sepsis induced the anxiety-like behavior and hippocampal-dependent cognitive impairment, as reflected by significantly increased distance spent in the open field test and decreased freezing time to context in the fear conditioning test. The abnormal behavioral changes co-occurred with significant increases in hippocampal IBA1-positive cells, IL-1β and IL-6 levels, and decreased NRG1, ErbB4, parvalbumin expressions, and evoked gamma activity. NRG1 treatment attenuated the sepsis-induced cognitive impairment and the associated biochemical markers, which were abolished by AG1478 administration. Notably, minocycline treatment attenuated neuroinflammation and mimicked the beneficial effects of NRG1 treatment. In summary, we provided additional evidence that the disruption of NRG1-ErbB4 signaling in the parvalbumin interneurons mediated by neuroinflammation might lead to abnormal gamma oscillations and thus contribute to cognitive impairment in a mouse model of SAE.

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Acknowledgments

This study was supported by grants from the National Science Foundation of China (Nos. 81300946 and 81471105).

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Authors and Affiliations

  1. Department of Emergency and Intensive Care Medicine, Nan**g Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nan**g University of Chinese Medicine, Nan**g, 210014, China

    Rong Gao & Run-hua Yang

  2. **ling Clinical Medical College of Nan**g Medical University, Nan**g, China

    Mu-huo Ji & Jian-jun Yang

  3. Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nan**g, China

    Mu-huo Ji & Jian-jun Yang

  4. Department of Anesthesiology, **ling Hospital, Medical School of Nan**g University, Nan**g, 210002, China

    Da-peng Gao & **-chun Shen

  5. Department of Anesthesiology, Nan**g Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nan**g University of Chinese Medicine, Nan**g, 210014, China

    Shao-gang Zhang

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  1. Rong Gao
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Correspondence to Jian-jun Yang or **-chun Shen.

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The study protocol was approved by the Ethics Committee of the Nan**g Integrated Traditional Chinese and Western Medicine Hospital, affiliated with the Nan**g University of Chinese Medicine, and all procedures were performed in accordance with the Guideline for the Care and Use of Laboratory Animals from the National Institutes of Health, USA.

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Gao, R., Ji, Mh., Gao, Dp. et al. Neuroinflammation-Induced Downregulation of Hippocampacal Neuregulin 1-ErbB4 Signaling in the Parvalbumin Interneurons Might Contribute to Cognitive Impairment in a Mouse Model of Sepsis-Associated Encephalopathy. Inflammation 40, 387–400 (2017). https://doi.org/10.1007/s10753-016-0484-2

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