Astrocyte regulation of amygdala circuit function

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Summary Astrocytes are the most abundant type of glial cell in the brain, playing vital roles in all facets of brain physiology. Given their central role in brain function, astrocytes have been implicated in a variety of psychiatric disorders including autism, anxiety, schizophrenia, depression, and suicide. Despite the progress in understanding the abnormalities in brain circuits and related molecular pathways, how astrocytes contribute to circuit dysfunction associated with psychiatric disorders remains nascent. Recent studies have shown that astrocytes play an essential role in amygdala function and associated behavioral outputs, which led us to further examine how amygdala astrocytes contribute to human depression and associated suicide. Towards this, we performed immunostaining from suicide decedents (N=20) and age-matched control, finding that the canonical astrocyte marker GFAP and a key astrocyte transcription factor NFIA are both drastically increased in the amygdala of suicide decedents. Recently, we reported that NFIA plays an essential role in the physiological activities of astrocytes, neuronal circuit activity, and brain function in the adult hippocampus. This evidence led us to hypothesize that astrocytic NFIA contributes to depression and associated suicide by regulating amygdala circuit function. To determine whether astrocytic NFIA affects amygdala circuit function and associated depressive behaviors, we utilized NFIA gain-of-function (GOF) and loss-of-function (LOF) mouse models. Preliminary studies revealed that NFIA GOF induced depressive/anxiety behaviors, while NFIA LOF suppressed these behaviors. In both cases, direct physiological analysis of amygdala circuit activity revealed significant and complementary alterations. Therefore, based on the strength of these preliminary data, we propose the following specific aims. In specific aim 1, we will determine the role of astrocytic NFIA in amygdala circuit activity and function using NFIA GOF and LOF mice models. In specific aim 2, we will decipher how astrocytic NFIA regulates amygdala circuits through GABA/MAOB. In this study, we will identify the target gene of NFIA using RNA-sequencing and manipulate the target gene with pharmacological/genetic tools. In specific aim 3, we will delineate astrocytic NFIA transcriptional networks in the amygdala. In this study, we will dissect the amygdala-specific NFIA transcriptional networks and confirm this in human samples.