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

Jessica L Bolton; 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

doi:10.1016/j.celrep.2022.110600

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

Cell Rep. 2022 Mar 29;38(13):110600. doi: 10.1016/j.celrep.2022.110600.

Authors

Affiliations

¹ Department of Pediatrics, University of California, Irvine, Irvine, CA, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA, USA. Electronic address: jbolton@gsu.edu.
² Department of Pediatrics, University of California, Irvine, Irvine, CA, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA, USA.
³ Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
⁴ Department of Pediatrics, University of California, Irvine, Irvine, CA, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA, USA; Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee, UK.
⁵ Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA, USA.
⁶ Département de Médecine Moléculaire, Université Laval, Québec City, QC, Canada; Axe Neurosciences, Centre de recherche du CHU de Québec, Québec City, QC, Canada.
⁷ Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee, UK.
⁸ Department of Pediatrics, University of California, Irvine, Irvine, CA, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. Electronic address: tallie@uci.edu.

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.

Keywords: 2-photon imaging; CP: Neuroscience; MerTK; chemogenetics; corticotropin-releasing factor; microglia; process dynamics; stress; synaptic pruning.

Publication types

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

MeSH terms

Animals
Corticotropin-Releasing Hormone*
Mice
Microglia / physiology
Neural Stem Cells*
Neurons / physiology
Synapses / physiology

Substances

Corticotropin-Releasing Hormone

Abstract

Publication types

MeSH terms

Substances

Grants and funding