TY - JOUR T1 - Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life JF - bioRxiv DO - 10.1101/2021.07.21.453252 SP - 2021.07.21.453252 AU - Jessica L. Bolton AU - Annabel K. Short AU - Shivashankar Othy AU - Cassandra L. Kooiker AU - Manlin Shao AU - Benjamin G. Gunn AU - Jaclyn Beck AU - Xinglong Bai AU - Stephanie M. Law AU - Julie C. Savage AU - Jeremy J. Lambert AU - Delia Belelli AU - Marie-Ève Tremblay AU - Michael D. Cahalan AU - Tallie Z. Baram Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/07/22/2021.07.21.453252.abstract N2 - The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.Competing Interest StatementThe authors have declared no competing interest. ER -