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

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 ont...

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Published in:Cell reports (Cambridge) 2022-03, Vol.38 (13), p.110600-110600, Article 110600
Main Authors: Bolton, Jessica L., Short, Annabel K., Othy, Shivashankar, Kooiker, Cassandra L., Shao, Manlin, Gunn, Benjamin G., Beck, Jaclyn, Bai, Xinglong, Law, Stephanie M., Savage, Julie C., Lambert, Jeremy J., Belelli, Delia, Tremblay, Marie-Ève, Cahalan, Michael D., Baram, Tallie Z.
Format: Article
Language:English
Subjects:
2-photon imaging
Animals
chemogenetics
corticotropin-releasing factor
Corticotropin-Releasing Hormone
MerTK
Mice
microglia
Microglia - physiology
Neural Stem Cells
Neurons - physiology
process dynamics
stress
Synapses - physiology
synaptic pruning
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Summary: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. [Display omitted] •Early-life stress (ELA) augments excitatory synapses on hypothalamic CRH cells•During ELA, the adjacent microglia poorly survey and prune synapses on CRH neurons•Mechanisms involve MerTK and yield aberrant hormonal and behavioral stress response•Chemogenetic microglial activation throughout ELA normalizes adult stress responses Early-life adversity (ELA) promotes lifelong aberrant stress responses and vulnerability to mental illnesses. Bolton et al. identify poor dynamics and hypothalamic CRH neurons’ excitatory synapse pruning of ELA microglia, implicating microglial MerTK. Chronic chemogenetic activation of ELA microglia normalized process dynamics, synapse density, and adult hormonal and behavioral stress responses.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2022.110600