Brain-Defective Insulin Signaling Is Associated to Late Cognitive Impairment in Post-Septic Mice

Abstract

Sepsis survivors frequently develop late cognitive impairment. Because little is known on the mechanisms of post-septic memory deficits, there are no current effective approaches to prevent or treat such symptoms. Here, we subjected mice to severe sepsis induced by cecal ligation and puncture (CLP) and evaluated the sepsis-surviving animals in the open field, novel object recognition (NOR), and step-down inhibitory avoidance (IA) task at different times after surgery. Post-septic mice (30 days post-surgery) failed in the NOR and IA tests but exhibited normal performance when re-evaluated 45 days after surgery. Cognitive impairment in post-septic mice was accompanied by reduced hippocampal levels of proteins involved in synaptic plasticity, including synaptophysin, cAMP response element-binding protein (CREB), CREB phosphorylated at serine residue 133 (CREBpSer¹³³), and GluA1 phosphorylated at serine residue 845 (GluA1pSer⁸⁴⁵). Expression of tumor necrosis factor α (TNF-α) was increased and brain insulin signaling was disrupted, as indicated by increased hippocampal IRS-1 phosphorylation at serine 636 (IRS-1pSer⁶³⁶) and decreased phosphorylation of IRS-1 at tyrosine 465 (IRS-1pTyr⁴⁶⁵), in the hippocampus 30 days after CLP. Phosphorylation of Akt at serine 473 (AktpSer⁴⁷³) and of GSK3 at serine 9 (GSK3βpSer⁹) were also decreased in hippocampi of post-septic animals, further indicating that brain insulin signaling is disrupted by sepsis. We then treated post-septic mice with liraglutide, a GLP-1 receptor agonist with insulinotropic activity, or TDZD-8, a GSK3β inhibitor, which rescued NOR memory. In conclusion, these results establish that hippocampal inflammation and disrupted insulin signaling are induced by sepsis and are linked to late memory impairment in sepsis survivors.

Keywords: Cognitive impairment; Glycogen synthase kinase 3 β (GSK3β); Insulin receptor substrate-1 (IRS-1) inhibition; Late cognitive impairment; Liraglutide; Sepsis survivors; TDZD-8.