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Disruption of Striatal-Enriched Protein Tyrosine Phosphatase Signaling Might Contribute to Memory Impairment in a Mouse Model of Sepsis-Associated Encephalopathy

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Abstract

Sepsis-associated encephalopathy (SAE) is a potentially irreversible acute cognitive dysfunction with unclear mechanism. Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase which normally opposes synaptic strengthening by regulating key signaling molecules involved in synaptic plasticity and neuronal function. Thus, we hypothesized that abnormal STEP signaling pathway was involved in sepsis-induced cognitive impairment evoked by lipopolysaccharides (LPS) injection. The levels of STEP, phosphorylation of GluN2B (pGluN2B), the kinases extracellular signal-regulated kinase 1/2 (pERK), cAMP-response element binding protein (CREB), synaptophysin, brain derived neurotrophic factor (BDNF), and post-synaptic density protein 95 (PSD95) in the hippocampus, prefrontal cortex, and striatum were determined at the indicated time points. In the present study, we found that STEP levels were significantly increased in the hippocampus, prefrontal cortex, and striatum following LPS injection, which might resulted from the disruption of the ubiquitin–proteasome system. Notably, a STEP inhibitor TC-2153 treatment alleviated sepsis-induced memory impairment by increasing phosphorylation of GluN2B and ERK1/2, CREB/BDNF, and PSD95. In summary, our results support the key role of STEP in sepsis-induced memory impairment in a mouse model of SAE, whereas inhibition of STEP may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81571083, 81771156, 81772126).

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  1. Man-man Zong and Hong-mei Yuan have contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China

    Man-man Zong, Xue He & Zhi-qiang Zhou

  2. Department of Anesthesiology, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China

    Hong-mei Yuan

  3. Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China

    Xiao-dong Qiu & Mu-huo Ji

  4. Department of Anesthesiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Jian-jun Yang

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  1. Man-man Zong
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Zong, Mm., Yuan, Hm., He, X. et al. Disruption of Striatal-Enriched Protein Tyrosine Phosphatase Signaling Might Contribute to Memory Impairment in a Mouse Model of Sepsis-Associated Encephalopathy. Neurochem Res 44, 2832–2842 (2019). https://doi.org/10.1007/s11064-019-02905-2

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