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

Date

2022

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.

Journal Title

Journal ISSN

Volume Title

Publisher

Cell Reports

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.

Description

We thank Dr. Ian Parker for access to the custom-built 2-photon microscope used for the live imaging. We thank Dr. Staci Bilbo (Duke University) and Dr. Carla Rothlin (Yale University) for the CX3CR1-BAC-Cre and the MerTK-fl/fl mice, respectively. We appreciate the excellent technical assistance of Emily Majorkiewicz, Andrew Quan Dong, Xinwen Li, Yanan Wu, Catherine Chiou, Keshav Suresh, Kathleen Guangying Zhou, Pouria Vadipour, Graciella Angeles, Johnathan Ho, Erin Card, and Jennifer Daglian, and we also thank Dr. Yoav Noam for his insight and support with kymograph analyses. The graphical abstract was created with BioRender.com.

Keywords

microglia, 2-photon imaging, process dynamics, synaptic pruning, stress, corticotropin-releasing factor, MerTK, chemogenetics

Citation

Bolton, J. L., Short, A. K., Othy, S., Kooiker, C. L., Shao, M., Gunn, B. G., ... Baram, T. Z. (2022). Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses. Cell Reports, 38(13), 110600. https://doi.org/10.1016/j.celrep.2022.110600