1. Academic Validation
  2. Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development

Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development

  • BMC Med. 2022 Jul 27;20(1):235. doi: 10.1186/s12916-022-02434-w.
Donghang Zhang  # 1 2 Yujiao Yang  # 3 Yaoxin Yang  # 1 2 Jin Liu 1 2 Tao Zhu 1 Han Huang 4 Cheng Zhou 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 2 Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 3 Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.
  • 4 Department of Anesthesiology & Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital of Sichuan University, Chengdu, 610041, China. han.huang@scu.edu.cn.
  • 5 Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China. zhouc@163.com.
  • # Contributed equally.
Abstract

Background: Neonatal sepsis can induce long-term cognitive impairment in adolescence or adulthood, but the underlying molecular mechanism is not fully understood. The expression of K+-Cl- co-transporter 2 (KCC2) plays a pivotal role in the GABAergic shift from depolarizing to hyperpolarizing during early postnatal development. In this study, we aimed to determine whether neonatal severe inflammation-induced cognitive impairment was associated with the expression of KCC2 during early development.

Methods: Neonatal severe inflammation was established by intraperitoneal injection of high dose lipopolysaccharide (LPS, 1 mg kg-1) in postnatal day 3 (P3) rats. The Morris water maze task and fear conditioning test were used to investigate long-term cognitive functions. ELISA, RT-PCR and Western blotting were used to examine the expression levels of proinflammatory cytokines and KCC2. Perforated patch-clamping recordings were used to determine the GABAergic shift.

Results: Neonatal severe inflammation led to long-term cognitive impairment in rats. Meanwhile, sustained elevation of interleukin-1 beta (IL-1β) levels was found in the hippocampus until P30 after LPS injection. Elevated expression of KCC2 and hyperpolarized GABA reversal potential (EGABA) were observed in CA1 hippocampal pyramidal neurons from the P7-P10 and P14-P16 rats after LPS injection. Specific knockdown of IL-1β mRNA expression rescued the elevated expression of KCC2 and the hyperpolarized EGABA at P7-P10 and P14-P16. Accordingly, specific knockdown of IL-1β or KCC2 expression improved the cognitive impairment induced by neonatal severe inflammation.

Conclusions: Sustained elevation of IL-1β in the hippocampus may induce cognitive impairment by upregulation of KCC2 during early development.

Keywords

Cognitive impairment; GABAergic shift; IL-1β; KCC2; Neonatal inflammation; Sepsis.

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