Author:
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,Durand-de Cuttoli Romain,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
Abstract
SummaryHyperexcitability 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.
Publisher
Cold Spring Harbor Laboratory