Layer-specific microglia activation drives chronic stress-induced synapse loss

Soteros, B. M.; Tillmon, H.; Wollet, M.; General, J.; Chin, H.; Lee, J. B.; Carreno, F. R.; Morilak, D. A.; Kim, J. H.; Sia, G. M.

doi:10.1101/2023.06.28.546889

bioRxiv · 10.1101/2023.06.28.546889

Layer-specific microglia activation drives chronic stress-induced synapse loss

Soteros, B. M.·Tillmon, H.·Wollet, M.·General, J.·Chin, H.·Lee, J. B.·Carreno, F. R.·Morilak, D. A.·Kim, J. H.·Sia, G. M.

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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 mouse medial prefrontal cortex (mPFC). 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.

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Soteros, B. M., Tillmon, H., Wollet, M., General, J., Chin, H., Lee, J. B., Carreno, F. R., Morilak, D. A., Kim, J. H., Sia, G. M.. 2023-06-30. Layer-specific microglia activation drives chronic stress-induced synapse loss. https://doi.org/10.1101/2023.06.28.546889

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