Related Experiment Video

Updated: May 9, 2026

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
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Neonatal microglia replacement in mice modulates seizure severity in adulthood

Carleigh A O'Brien1, Samuelle A S Delcy2, Sangeeta Shukla3

  • 1Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|August 28, 2025
PubMed

Insights

Early life microglia depletion worsens brain injury, but replacement with monocytes can restore function. Donor microglia transfer did not improve outcomes, highlighting the importance of cell origin in microglia replacement therapy for pediatric neurologic diseases.

Area of Science:

  • Neuroscience
  • Immunology
  • Developmental Biology

Background:

  • Microglia replacement therapy is a promising approach for pediatric neurologic diseases.
  • The long-term effects of early-life microglia manipulation on neural circuits are not well understood.

Purpose of the Study:

  • To investigate the durable impacts of early postnatal microglia depletion and adoptive macrophage transfer on neural circuits in a mouse model.
  • To determine how different macrophage populations affect brain responses to excitotoxic challenge.

Main Methods:

  • Established pharmacologic and genetic models for neonatal microglia depletion and replacement.
  • Utilized a chemical seizure model to assess seizure severity, mortality, and neuropathology.
  • Performed RNA sequencing on transplanted microglia, monocyte-derived surrogates, and endogenous microglia.

Main Results:

  • Postnatal microglia depletion exacerbated seizure severity, mortality, and neuropathology in adult mice.
  • Adoptive transfer of monocytes rescued the detrimental effects of microglia depletion.
  • Transfer of donor microglia did not rescue, and even worsened, seizure phenotypes.
  • RNA sequencing revealed distinct transcriptional responses of different macrophage populations to excitotoxic insult.

Conclusions:

  • Neonatal microglia depletion has lasting negative effects on the brain.
  • Monocyte-derived macrophages can effectively replace endogenous microglia and restore function.
  • The ontogeny and source of macrophages significantly influence their response to brain injury.
  • Findings provide critical insights for the preclinical development of microglia replacement therapies.
Keywords:
cell therapiesleukodystrophiesmicrogliamicroglia replacementneuroinflammationseizure

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