Acute Transient Cognitive Dysfunction and Acute Brain Injury Induced by Systemic Inflammation Occur by Dissociable IL-1-dependent Mechanisms

Mol Psychiatry. 2019 Oct;24(10):1533-1548. doi: 10.1038/s41380-018-0075-8. Epub 2018 Jun 6.

Abstract

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1β replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1β but direct hippocampal action of IL-1β causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain Injuries / immunology*
  • Cognition / physiology
  • Cognition Disorders / immunology
  • Cognitive Dysfunction / chemically induced
  • Cognitive Dysfunction / immunology*
  • Cognitive Dysfunction / metabolism
  • Cytokines / metabolism
  • Dementia / immunology
  • Female
  • Hippocampus / metabolism
  • Inflammation / complications
  • Inflammation / metabolism
  • Interleukin-1 / immunology
  • Interleukin-1 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Memory Disorders / immunology
  • Memory, Short-Term / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism

Substances

  • Cytokines
  • Interleukin-1
  • Lipopolysaccharides