Microglia and Memory: Modulation by Early-Life Infection

J Neurosci. 2011 Oct 26;31(43):15511-21. doi: 10.1523/JNEUROSCI.3688-11.2011.

Abstract

The proinflammatory cytokine interleukin-1β (IL-1β) is critical for normal hippocampus (HP)-dependent cognition, whereas high levels can disrupt memory and are implicated in neurodegeneration. However, the cellular source of IL-1β during learning has not been shown, and little is known about the risk factors leading to cytokine dysregulation within the HP. We have reported that neonatal bacterial infection in rats leads to marked HP-dependent memory deficits in adulthood. However, deficits are only observed if unmasked by a subsequent immune challenge [lipopolysaccharide (LPS)] around the time of learning. These data implicate a long-term change within the immune system that, upon activation with the "second hit," LPS, acutely impacts the neural processes underlying memory. Indeed, inhibiting brain IL-1β before the LPS challenge prevents memory impairment in neonatally infected (NI) rats. We aimed to determine the cellular source of IL-1β during normal learning and thereby lend insight into the mechanism by which this cytokine is enduringly altered by early-life infection. We show for the first time that CD11b(+) enriched cells are the source of IL-1β during normal HP-dependent learning. CD11b(+) cells from NI rats are functionally sensitized within the adult HP and produce exaggerated IL-1β ex vivo compared with controls. However, an exaggerated IL-1β response in vivo requires LPS before learning. Moreover, preventing microglial activation during learning prevents memory impairment in NI rats, even following an LPS challenge. Thus, early-life events can significantly modulate normal learning-dependent cytokine activity within the HP, via a specific, enduring impact on brain microglial function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acoustic Stimulation / methods
  • Animals
  • Animals, Newborn
  • Anti-Bacterial Agents / therapeutic use
  • Bacterial Infections / complications*
  • Bacterial Infections / drug therapy
  • Bacterial Infections / pathology*
  • Brain / metabolism
  • Brain / pathology
  • CD11b Antigen / metabolism
  • CX3C Chemokine Receptor 1
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Cues
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay / methods
  • Exploratory Behavior / drug effects
  • Fear
  • Female
  • Flow Cytometry
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glial Fibrillary Acidic Protein / metabolism
  • In Vitro Techniques
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / adverse effects
  • Male
  • Memory Disorders / etiology*
  • Microglia / drug effects
  • Microglia / metabolism*
  • Minocycline / therapeutic use
  • Neural Inhibition / drug effects
  • Pregnancy
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Chemokine / metabolism

Substances

  • Anti-Bacterial Agents
  • CD11b Antigen
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, rat
  • Glial Fibrillary Acidic Protein
  • Interleukin-1beta
  • Lipopolysaccharides
  • RNA, Messenger
  • Receptors, Chemokine
  • Minocycline