Fulton Sasha L, Bendl Jaroslav, Gameiro-Ros Isabel, Fullard John F, Al-Kachak Amni, Lepack Ashley E, Stewart Andrew F, Singh Sumnima, Poller Wolfram C, Bastle Ryan M, Hauberg Mads E, Fakira Amanda K, Chen Min, Cuttoli Romain Durand-de, Cathomas Flurin, Ramakrishnan Aarthi, Gleason Kelly, Shen Li, Tamminga Carol A, Milosevic Ana, Russo Scott J, Swirski Filip, Blitzer Robert D, Slesinger Paul A, Roussos Panos, Maze Ian
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
bioRxiv. 2023 May 4:2023.05.04.539425. doi: 10.1101/2023.05.04.539425.
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.
眶额叶皮质（OFC）的兴奋性过高是重度抑郁症（MDD）快感缺失领域的关键临床特征。然而，这种功能障碍背后的细胞和分子基础仍然未知。在这里，对人类OFC进行的细胞群体特异性染色质可及性分析意外地将MDD的遗传风险完全定位到非神经元细胞，转录组分析揭示了该区域明显的胶质细胞失调。对MDD特异性顺式调控元件的表征确定ZBTB7A（一种星形胶质细胞反应性的转录调节因子）是MDD特异性染色质可及性和基因表达的重要介质。在小鼠OFC中的基因操作表明，星形胶质细胞的Zbtb7a对于促进行为缺陷、细胞类型特异性转录和染色质谱以及由慢性应激（MDD的主要风险因素）诱导的OFC神经元兴奋性过高既是必要的也是充分的。因此，这些数据突出了OFC星形胶质细胞在应激易感性中的关键作用，并确定ZBTB7A是MDD中一个关键的失调因子，它介导了驱动OFC兴奋性过高的适应性不良星形胶质细胞功能。
