Major-depressive-disorder-associated dysregulation of ZBTB7A in orbitofrontal cortex promotes astrocyte-mediated stress susceptibility

Sasha L Fulton; Jaroslav Bendl; Giuseppina Di Salvo; John F Fullard; Amni Al-Kachak; Ashley E Lepack; Andrew F Stewart; Sumnima Singh; Wolfram F Poller; Ryan M Bastle; Mads E Hauberg; Amanda K Fakira; Vishwendra Patel; Min Chen; Romain Durand-de Cuttoli; Isabel Gameiro-Ros; Flurin Cathomas; Aarthi Ramakrishnan; Kelly Gleason; Li Shen; Carol A Tamminga; Ana Milosevic; Scott J Russo; Filip K Swirski; Paul A Slesinger; Ishmail Abdus-Saboor; Robert D Blitzer; Panos Roussos; Ian Maze

doi:10.1016/j.neuron.2025.05.023

Major-depressive-disorder-associated dysregulation of ZBTB7A in orbitofrontal cortex promotes astrocyte-mediated stress susceptibility

Neuron. 2025 Jun 11:S0896-6273(25)00394-0. doi: 10.1016/j.neuron.2025.05.023. Online ahead of print.

Authors

Sasha L Fulton¹, Jaroslav Bendl², Giuseppina Di Salvo³, John F Fullard², Amni Al-Kachak³, Ashley E Lepack³, Andrew F Stewart³, Sumnima Singh⁴, Wolfram F Poller⁴, Ryan M Bastle³, Mads E Hauberg⁵, Amanda K Fakira³, Vishwendra Patel⁶, Min Chen³, Romain Durand-de Cuttoli³, Isabel Gameiro-Ros³, Flurin Cathomas³, Aarthi Ramakrishnan³, Kelly Gleason⁷, Li Shen³, Carol A Tamminga⁷, Ana Milosevic⁸, Scott J Russo³, Filip K Swirski⁴, Paul A Slesinger³, Ishmail Abdus-Saboor⁹, Robert D Blitzer¹⁰, Panos Roussos¹¹, Ian Maze¹²

Affiliations

¹ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Zuckerman Institute of Mind, Brain, and Behavior, Columbia University, New York, NY, USA.
² Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
⁸ Laboratory of Developmental Genetics, Rockefeller University, New York, NY, USA.
⁹ Zuckerman Institute of Mind, Brain, and Behavior, Columbia University, New York, NY, USA.
¹⁰ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, New York, NY, USA; Mental Illness Research Education and Clinical Center, James J. Peters VA Medical Center, Bronx, New York, NY, USA.
¹² Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: ian.maze@mssm.edu.

Abstract

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.

Keywords: ZBTB7A; anhedonia; astrocyte-neuron communication; astrocytes; chronic social defeat stress; epigenomics; major depressive disorder; orbitofrontal cortex.

Abstract

Grants and funding