Astrocytic ZBTB7A promotes orbitofrontal cortex dysfunction associated with Major Depressive Disorder

Overall risk for Major Depressive Disorder (MDD) is determined by complex interactions between genetic and environmental factors that influence epigenetic regulation of neuroplasticity and stress pathways. These mechanisms are specific to the distinct regulatory context within regionally-defined brain cell-types. Here, we employed genome-wide chromatin accessibility profiling of neuronal vs. non-neuronal cells in orbitofrontal cortex (OFC) to capture regulatory signatures of MDD. We mapped genetic risk for MDD to active promoters of non-neuronal cell-types in OFC and identified MDD-specific open chromatin regions, which were differentially accessible exclusively in non-neuronal cells. Characterization of these loci revealed a key role for astrocyte dysfunction, and implicated the chromatin remodeling protein ZBTB7A, which coordinates wide-ranging cellular activation programs, including NF-kB inflammatory transcription. In mice, astrocyte-specific knockdown of Zbtb7a reversed chromatin remodeling, reactive astrocyte transcription, and behavioral deficits associated with chronic stress. Conversely, ZBTB7A overexpression in OFC astrocytes induced stress-related behavioral deficits, promoted widespread inflammatory gene expression, and drove pathophysiological OFC neuronal hyperactivity in response to a mild subthreshold stressor. Our data highlight a critical role for OFC astrocytes in the bidirectional regulation of stress vulnerability and pinpoint ZBTB7A as a key factor mediating maladaptive astrocyte plasticity and OFC neuronal hyperexcitability in MDD. Overall design: For Zbtb7a knockdown experiments: following bilateral intra-OFC injection of either the AAV6-GFAP-Zbtb7a-KD-mir virus or the AAV6-GFAP-mirNeg control virus to knockdown Zbtb7a expression specifically in OFC astrocytes, mice were randomly assigned to either the control group, or chronic stress group (10 days of chronic social defeat stress). For ZBTB7A-OE experiments: following bilateral intra-OFC injection of either the AAV6-GFAP-ZBTB7A OE virus or the AAV6-GFAP-GFP empty vector control virus to overexpress ZBTB7A specifically in OFC astrocytes, mice were randomly assigned to either the control group, or acute stress group (1 day of social defeat stress).