Interleukin-1β Modulates Synaptic Transmission and Synaptic Plasticity During the Acute Phase of Sepsis in the Senescence-Accelerated Mouse Hippocampus

Abstract

BackgroundAging and pre-existing cognitive impairment are considered to be independent risk factors for sepsis-associated encephalopathy. This study aimed to investigate the manner in which aging and pre-existing cognitive dysfunction modified neuroinflammation, synaptic plasticity, and basal synaptic transmission during the acute phase of sepsis using Senescence-Accelerated Mice Prone 8 (SAMP8) and Senescence-Accelerated Resistant Mice 1 (SAMR1).MethodsWe used 6-month-old SAMP8 and SAMR1. Sepsis was induced using cecal ligation and puncture (CLP). The animal’s hippocampi and blood were collected for subsequent investigations 24 h after surgery.ResultsLong-term potentiation (LTP) was impaired in the Shaffer-collateral (SC)-CA1 pathway of the hippocampus in SAMP8 without surgery compared to the age-matched SAMR1, which was reflective of cognitive dysfunction in SAMP8. CLP impaired the SC-CA1 LTP in SAMR1 compared to the sham-operated controls, but not in SAMP8. Moreover, CLP decreased the input-output curve and increased the paired-pulse ratio in SAMP8, suggesting the reduced probability of basal synaptic transmission due to sepsis. Immunohistochemical analysis revealed that CLP elevated IL-1β levels, especially in the hippocampi of SAMP8 with microglial activation. In vivo peripheral IL-1 receptor antagonist (IL-1ra) administration in the septic SAMP8 revealed that the neuroinflammation was not correlated with the peripheral elevation of IL-1β. Ex vivo IL-1ra administration to the hippocampus ameliorated LTP impairment in SAMR1 and the reduction in basal transmission in SAMP8 after sepsis.ConclusionsThe mechanism of the modulation of synaptic transmission and synaptic plasticity by the acute stage of sepsis differed between SAMR1 and SAMP8. These changes were related to centrally derived IL-1 receptor-mediated signaling and were accompanied by microglial activation, especially in SAMP8.

Environmental Enrichment Protects Against Sepsis-Associated Encephalopathy-Induced Learning and Memory Deficits by Enhancing the Synthesis and Release of Vasopressin in the Supraoptic Nucleus

“… 73 Increased IL-1β levels result in the impairment of long-term potentiation (LTP), which is the electrophysiological marker of learning and memory. 74 IL-6 is also widely reported to participate in the impairment of learning and memory. Blocking IL-6 led to a prolonged LTP and improved memory in a Y-maze task.…”

Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation

“…Any of these may serve as targets for rescue strategies of disordered synaptic function and eventually help to improve inflammation-induced cognitive decline. First, we identified defective synaptic plasticity as a crucial pathogenic mechanism of long-term cognitive dysfunction in SAE persisting beyond acute brain inflammation 52 . More specifically, we uncovered distinct changes in the regulation of synaptic proteins leading to dysfunctional basal synaptic transmission and scaling and defective LTP.…”

Insight Into Regulatory T Cells in Sepsis-Associated Encephalopathy

“…From a clinical point a view, the disease course of SAE can be divided into acute and chronic phase ( 7 , 9 , 11 , 14 , 15 ). The acute phase of SAE is commonly characterized by delirium symptoms and acute changes in patient's consciousness ( 7 , 9 , 16 , 17 ) and by the occurrence of different complex pathophysiological mechanisms, including uncontrolled neuroinflammation, as result of neutrophils, monocytes and resident glial cells activation and infiltration; long-term expression of multiple cytokines and chemokine genes, also called “cytokine storm” ( 18 ) and is thought to be the major cause of organ dysfunction and acute symptoms like fever, fatigue and anorexia; and enhanced T helper (Th)1 and Th17 cells activity ( 4 ) ( Figure 1 ).…”

“…The acute phase of SAE is commonly characterized by delirium symptoms and acute changes in patient's consciousness ( 7 , 9 , 16 , 17 ) and by the occurrence of different complex pathophysiological mechanisms, including uncontrolled neuroinflammation, as result of neutrophils, monocytes and resident glial cells activation and infiltration; long-term expression of multiple cytokines and chemokine genes, also called “cytokine storm” ( 18 ) and is thought to be the major cause of organ dysfunction and acute symptoms like fever, fatigue and anorexia; and enhanced T helper (Th)1 and Th17 cells activity ( 4 ) ( Figure 1 ). These lead to dysfunction and massive apoptosis of brain cells, especially microglia, astrocytes, neurons and cerebral endothelial cells (CECs) ( 15 , 19 , 20 ). Indeed/accordingly, a study by Saito et al ( 12 ) showed that in a cecal slurry (CS)-induced septic mouse model, neutrophils infiltration, an hallmark feature of SAE acute phase, favors CD4 + and CD8 + T cells accumulation, microglial activation and neuroinflammation (IL-1β and IL-6) in the cerebral cortex, BBB disruption, and increase anxiety-like symptoms.…”

“…Ischemic processes/injury have been, together with neuroinflammation, identified as playing a critical role in SAE pathogenesis. These mechanisms are directly associated with BBB disruption, brain edema, monocytes and macrophages infiltration, astrogliosis and brain cells apoptosis ( 11 , 14 , 15 ). The aforementioned issues raise the hypothesis that early targeting of the inflammatory signaling may have a potential therapeutic role in the protection against the acute phase of SAE.…”