Microglia regulate the number of neural precursor cells in the developing cerebral cortex

J Neurosci. 2013 Mar 6;33(10):4216-33. doi: 10.1523/JNEUROSCI.3441-12.2013.


Neurogenesis must be properly regulated to ensure that cell production does not exceed the requirements of the growing cerebral cortex, yet our understanding of mechanisms that restrain neuron production remains incomplete. We investigated the function of microglial cells in the developing cerebral cortex of prenatal and postnatal macaques and rats and show that microglia limit the production of cortical neurons by phagocytosing neural precursor cells. We show that microglia selectively colonize the cortical proliferative zones and phagocytose neural precursor cells as neurogenesis nears completion. We found that deactivating microglia in utero with tetracyclines or eliminating microglia from the fetal cerebral cortex with liposomal clodronate significantly increased the number of neural precursor cells, while activating microglia in utero through maternal immune activation significantly decreased the number of neural precursor cells. These data demonstrate that microglia play a fundamental role in regulating the size of the precursor cell pool in the developing cerebral cortex, expanding our understanding of the mechanisms that regulate cortical development. Furthermore, our data suggest that any factor that alters the number or activation state of microglia in utero can profoundly affect neural development and affect behavioral outcomes.

Publication types

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

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Calcium-Binding Proteins / metabolism
  • Cell Count
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / embryology*
  • Cerebral Cortex / growth & development*
  • Cerebral Cortex / transplantation
  • Cerebral Ventricles / cytology
  • Cerebral Ventricles / embryology
  • Cerebral Ventricles / growth & development
  • Embryo, Mammalian
  • Female
  • HLA-DR Antigens / metabolism
  • Indoles / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / toxicity
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Macaca
  • Male
  • Microfilament Proteins / metabolism
  • Microglia / physiology*
  • Microscopy, Confocal
  • Minocycline / pharmacology
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / physiology*
  • Neurogenesis / physiology
  • Nitric Oxide Synthase Type II / metabolism
  • Phagocytosis / physiology
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / pathology*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Rats
  • T-Box Domain Proteins / metabolism


  • Aif1 protein, rat
  • Calcium-Binding Proteins
  • HLA-DR Antigens
  • Indoles
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Luminescent Proteins
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Proliferating Cell Nuclear Antigen
  • T-Box Domain Proteins
  • fluorescent protein 583
  • DAPI
  • Nitric Oxide Synthase Type II
  • Minocycline