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.
Highlights
MATERIALS AND METHODSSepsis causes multiple-organ dysfunction via dysregulation of the host response to infection, and the brain is often one of the first organs affected by sepsis (Pytel and Alexander, 2009)
We previously reported that long-term potentiation (LTP) in the mouse hippocampus, which could be regarded as the cellular basis of learning and memory (Bliss and Collingridge, 1993), was impaired via mechanisms associated with microglial activation and interleukin (IL)-1β activity during the acute phase of sepsis (Hoshino et al, 2017b)
Several studies have demonstrated the relationship between neuroinflammation and cognitive dysfunction caused by sepsis using healthy aging animals (Barrientos et al, 2015), to the best of our knowledge, no study has explored the influence of sepsis on synaptic function using an animal model of aging combined with cognitive dysfunction
Summary
MATERIALS AND METHODSSepsis causes multiple-organ dysfunction via dysregulation of the host response to infection, and the brain is often one of the first organs affected by sepsis (Pytel and Alexander, 2009). Sepsis-associated encephalopathy (SAE) is defined as diffuse brain dysfunction accompanied by sepsis, in the absence of direct central nervous system infection, which manifests as cognitive dysfunction, especially learning and memory disabilities (Gofton and Young, 2012; Widmann and Heneka, 2014). We previously reported that long-term potentiation (LTP) in the mouse hippocampus, which could be regarded as the cellular basis of learning and memory (Bliss and Collingridge, 1993), was impaired via mechanisms associated with microglial activation and interleukin (IL)-1β activity during the acute phase of sepsis (Hoshino et al, 2017b). Aging 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)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
