Major-depressive-disorder-associated dysregulation of ZBTB7A in orbitofrontal cortex promotes astrocyte-mediated stress susceptibility
Heightened activity in the orbitofrontal cortex (OFC), a brain region that contributes to motivation, emotion, and reward-related decision-making, is a key clinical feature of major depressive disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unclear. Here, we performed cell-type-specific profiling of human OFC and unexpectedly mapped MDD-linked epigenomic features (including genetic risk variants) to non-neuronal cells, revealing significant glial dysregulation in this region. Characterization of MDD-specific chromatin loci further identified ZBTB7A-a transcriptional regulator of astrocyte reactivity-as an important mediator of MDD-related alterations. In rodent models, we found that Zbtb7a induction in astrocytes is both necessary and sufficient to drive stress-mediated behavioral deficits, cell-type-specific transcriptional/epigenomic signatures, and aberrant OFC astrocyte-neuronal communication in male mice-an established MDD risk factor. These findings thus highlight essential roles for astrocytes in OFC-mediated stress susceptibility and identify ZBTB7A as a critical and therapeutically relevant regulator of MDD-related OFC dysfunction.
Authors
- Romain Durand-de Cuttoli (ORCID: https://orcid.org/0000-0003-0240-7608)
- Ian Maze (ORCID: https://orcid.org/0000-0003-1490-7781)
- Sasha L. Fulton (ORCID: https://orcid.org/0000-0003-3626-7412)
- Wolfram C. Poller (ORCID: https://orcid.org/0000-0002-4632-5551)
- Amni Al-Kachak (ORCID: https://orcid.org/0000-0002-3155-8520)
- Kelly Gleason
- Amanda K. Fakira (ORCID: https://orcid.org/0000-0001-7626-3833)
- John F. Fullard (ORCID: https://orcid.org/0000-0001-9874-2907)
- Mads E. Hauberg (ORCID: https://orcid.org/0000-0003-4873-2764)
- Filip K. Świrski (ORCID: https://orcid.org/0000-0002-3163-9152)
- Scott J. Russo (ORCID: https://orcid.org/0000-0002-6470-1805)
- Ishmail Abdus-Saboor (ORCID: https://orcid.org/0000-0003-2120-0063)
- Andrew F. Stewart (ORCID: https://orcid.org/0000-0001-7866-5959)
- Vishwendra Patel
- Flurin Cathomas (ORCID: https://orcid.org/0000-0002-8274-1317)
- Jaroslav M. Bendl (ORCID: https://orcid.org/0000-0001-9989-2720)
- Ryan M. Bastle (ORCID: https://orcid.org/0000-0003-3184-0398)
- Robert D. Blitzer (ORCID: https://orcid.org/0000-0001-8829-1532)
- Panos Roussos (ORCID: https://orcid.org/0000-0002-4640-6239)
- Ashley E. Lepack (ORCID: https://orcid.org/0000-0003-2972-5286)
- Paul A. Slesinger
- Sumnima Singh (ORCID: https://orcid.org/0000-0002-1826-0180)
- Ana Milošević (ORCID: https://orcid.org/0000-0002-1380-0870)
- Isabel Gameiro‐Ros (ORCID: https://orcid.org/0000-0002-8286-2928)
- Li Shen (ORCID: https://orcid.org/0000-0002-5443-0503)
- Min Chen (ORCID: https://orcid.org/0000-0002-0676-3143)
- Aarthi Ramakrishnan
- G. Salvo (ORCID: https://orcid.org/0009-0001-6948-4619)
- C.A. Tamminga
Institutions
- Allen Institute for Brain Science (US)
- Southwestern Medical Center (US)
- MIND Research Institute (US)
- Southwestern Medical Center (US)
- Rockefeller University (US)
- The University of Texas Southwestern Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Neuron
- Published
- 2025-06-13
- DOI
- https://doi.org/10.1016/j.neuron.2025.05.023
- Citations
- 3
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.73
Funders
- Howard Hughes Medical Institute
- Burroughs Wellcome Fund
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke