Minocycline causes widespread cell death and increases microglial labeling in the neonatal mouse brain

Dev Neurobiol. 2017 Jun;77(6):753-766. doi: 10.1002/dneu.22457. Epub 2016 Oct 14.


Minocycline, an antibiotic of the tetracycline family, inhibits microglia in many paradigms and is among the most commonly used tools for examining the role of microglia in physiological processes. Microglia may play an active role in triggering developmental neuronal cell death, although findings have been contradictory. To determine whether microglia influence developmental cell death, we treated perinatal mice with minocycline (45 mg/kg) and quantified effects on dying cells and microglial labeling using immunohistochemistry for activated caspase-3 (AC3) and ionized calcium-binding adapter molecule 1 (Iba1), respectively. Contrary to our expectations, minocycline treatment from embryonic day 18 to postnatal day (P)1 caused a > tenfold increase in cell death 8 h after the last injection in all brain regions examined, including the primary sensory cortex, septum, hippocampus and hypothalamus. Iba1 labeling was also increased in most regions. Similar effects, although of smaller magnitude, were seen when treatment was delayed to P3-P5. Minocycline treatment from P3 to P5 also decreased overall cell number in the septum at weaning, suggesting lasting effects of the neonatal exposure. When administered at lower doses (4.5 or 22.5 mg/kg), or at the same dose 1 week later (P10-P12), minocycline no longer increased microglial markers or cell death. Taken together, the most commonly used microglial "inhibitor" increases cell death and Iba1 labeling in the neonatal mouse brain. Minocycline is used clinically in infant and pediatric populations; caution is warrented when using minocycline in developing animals, or extrapolating the effects of this drug across ages. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 753-766, 2017.

Keywords: cell death; cortex; hippocampus; hypothalamus; microglia; minocycline; septum.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Anti-Bacterial Agents / pharmacology*
  • Body Weight / drug effects
  • Brain / cytology*
  • Calcium-Binding Proteins / metabolism
  • Caspase 3 / metabolism
  • Cell Count
  • Cell Death / drug effects*
  • Dose-Response Relationship, Drug
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins / metabolism
  • Microglia / drug effects*
  • Minocycline / pharmacology*


  • Aif1 protein, mouse
  • Anti-Bacterial Agents
  • Calcium-Binding Proteins
  • Microfilament Proteins
  • Caspase 3
  • Minocycline