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

TitleEarly stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses.
Publication TypeJournal Article
Year of Publication2022
AuthorsBolton, JL, Short, AK, Othy, S, Kooiker, CL, Shao, M, Gunn, BG, Beck, J, Bai, X, Law, SM, Savage, JC, Lambert, JJ, Belelli, D, Tremblay, M-È, Cahalan, MD, Baram, TZ
JournalCell Rep
Volume38
Issue13
Pagination110600
Date Published2022 Mar 29
ISSN2211-1247
KeywordsAnimals, Corticotropin-Releasing Hormone, Mice, Microglia, Neural Stem Cells, Neurons, Synapses
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.

DOI10.1016/j.celrep.2022.110600
Alternate JournalCell Rep
PubMed ID35354026