Dataset Information

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

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 (E_GABA) 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 E_GABA 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.

SUBMITTER: Zhang D

PROVIDER: S-EPMC9327322 | biostudies-literature |

REPOSITORIES: biostudies-literature

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