Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses

Jessica L. Bolton (Lead / Corresponding author), Annabel K. Short, Shivashankar Othy, Cassandra L. Kooiker, Manlin Shao, Benjamin G. Gunn, Jaclyn Beck, Xinglong Bai, Stephanie M. Law, Julie C. Savage, Jeremy J. Lambert, Delia Belelli, Marie-Ève Tremblay, Michael D. Cahalan, Tallie Z. Baram (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)
143 Downloads (Pure)

Abstract

Several mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, provoking these enduring vulnerabilities. We find that ELA increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning by adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Notably, selective early-life activation of ELA microglia normalized adult acute and chronic stress responses, including stress-induced hormone secretion and behavioral threat responses, as well as chronic adrenal hypertrophy of ELA mice. Thus, microglial actions during development are powerful contributors to mechanisms by which ELA sculpts the connectivity of stress-regulating neurons, promoting vulnerability to stress and stress-related mental illnesses.

Original languageEnglish
Article number110600
Number of pages24
JournalCell Reports
Volume38
Issue number13
DOIs
Publication statusPublished - 29 Mar 2022

Keywords

  • Animals
  • Corticotropin-Releasing Hormone
  • Mice
  • Microglia/physiology
  • Neural Stem Cells
  • Neurons/physiology
  • Synapses/physiology
  • stress
  • process dynamics
  • CP: Neuroscience
  • corticotropin-releasing factor
  • chemogenetics
  • synaptic pruning
  • 2-photon imaging
  • MerTK
  • microglia

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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