Complement and microglia activation mediate stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex in male mice

Haven Tillmon, Breeanne M. Soteros, Liang Shen, Qifei Cong, Mackenna Wollet, Julianne General, Hanna Chin, John Beichen Lee, Flavia R. Carreno, David A. Morilak, Jun Hee Kim, Gek Ming Sia

Research output: Contribution to journalArticlepeer-review

Abstract

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the medial prefrontal cortex (mPFC) in male mice. Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.

Original languageEnglish (US)
Article number9803
JournalNature communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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