ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex

Fulton, S. L.; Bendl, J.; Gameiro-Ros, I.; Fullard, J. F.; Al-Kachak, A.; Lepack, A. E.; Stewart, A. F.; Singh, S.; Poller, W. C.; Bastle, R. M.; Hauberg, M. E.; Fakira, A. K.; Chen, M.; Durand-de Cuttoli, R.; Cathomas, F.; Ramakrishnan, A.; Gleason, K.; Shen, L.; Tamminga, C. A.; Milosevic, A.; Russo, S. J.; Swirski, F.; Blitzer, R. D.; Slesinger, P. A.; Roussos, P.; Maze, I.

doi:10.1101/2023.05.04.539425

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bioRxiv · 10.1101/2023.05.04.539425

ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex

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Abstract

Hyperexcitability in the orbitofrontal cortex (OFC) is a key clinical feature of anhedonic domains of Major Depressive Disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unknown. Here, cell-population-specific chromatin accessibility profiling in human OFC unexpectedly mapped genetic risk for MDD exclusively to non-neuronal cells, and transcriptomic analyses revealed significant glial dysregulation in this region. Characterization of MDD-specific cis-regulatory elements identified ZBTB7A - a transcriptional regulator of astrocyte reactivity - as an important mediator of MDD-specific chromatin accessibility and gene expression. Genetic manipulations in mouse OFC demonstrated that astrocytic Zbtb7a is both necessary and sufficient to promote behavioral deficits, cell-type-specific transcriptional and chromatin profiles, and OFC neuronal hyperexcitability induced by chronic stress - a major risk factor for MDD. These data thus highlight a critical role for OFC astrocytes in stress vulnerability and pinpoint ZBTB7A as a key dysregulated factor in MDD that mediates maladaptive astrocytic functions driving OFC hyperexcitability.

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Fulton, S. L., Bendl, J., Gameiro-Ros, I., Fullard, J. F., Al-Kachak, A., Lepack, A. E., Stewart, A. F., Singh, S., Poller, W. C., Bastle, R. M., Hauberg, M. E., Fakira, A. K., Chen, M., Durand-de Cuttoli, R., Cathomas, F., Ramakrishnan, A., Gleason, K., Shen, L., Tamminga, C. A., Milosevic, A., Russo, S. J., Swirski, F., Blitzer, R. D., Slesinger, P. A., Roussos, P., Maze, I.. 2023-05-04. ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex. https://doi.org/10.1101/2023.05.04.539425

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