Transcriptional Control of Gliogenesis in the CNS

摘要

Abstract The goal of the parent grant is to understand the transcriptional mechanisms that control the physiological functions of astrocytes in the brain. The transcription factor Nuclear Factor I-A (NFIA) is the focal point of the parent grant and we propose to determine its role in maintaining astrocyte physiology and neuronal circuits across a host of brain regions. These topics are particularly relevant to the pathogenesis of Alzheimer’s Disease (AD) as patients with AD have reactive astrocytes closely associated with degenerating neurons across multiple brain regions; these observations have been recapitulated in mouse models of AD. Despite these clear links between AD pathology and astrocytes, evaluation of astrocyte phenotypes in AD typically focuses on GFAP upregulation and various, poorly defined states of reactivity. These broad molecular criteria overlook how pathological states manifest in AD disrupt normal astrocyte function and their essential interactions with neurons during the formative stages of disease and throughout progression. Therefore, the overarching goal of this supplement is to bring tools developed in the parent grant to bear on mouse models of AD in order to decipher how physiological changes in astrocytes contribute to AD pathogenesis. We have generated a set of mouse tools and developed a platform for comprehensively evaluating astrocyte physiology and contributions to established circuits that we will apply to mouse models of AD. In the first aim, we will decipher how astrocyte physiology and their interactions with neurons change across of a series of landmark timepoints in mouse models of AD. Here we will assess a battery of functional criteria including: morphology, Ca2+ activities, proximity to neurons, handling of neurotransmitters, and activity of associated neurons. In the second aim, we will use our mouse tools to evaluate the role of astrocytic NFIA in AD pathogenesis. Using these tools, we discovered that astrocytic NFIA plays an essential role in maintaining astrocyte function and regulating hippocampal circuits, a brain region that is vulnerable to AD. Moreover, NFIA is highly expressed in reactive astrocytes found in human neurological diseases. Using these observations as our premise, we will determine the expression of NFIA in reactive astrocytes in human AD, how its loss modifies pathological benchmarks of AD, and how AD modifies astrocytic NFIA function. Upon completion of this supplement these studies will reveal when physiological changes in astrocytes take root during AD pathogenesis and how NFIA contributes to these changes in astrocytes.