Our studies on astrocyte diversity in the adult brain, revealed that NFIA is highly expressed in adult astrocytes, across several brain regions. This led us to hypothesize that, in addition to its pivotal role in astrocyte development, NFIA may also contribute to astrocyte function in the adult. This hypothesis addresses a key ?gap area? in our knowledge of astrocyte biology as the transcriptional mechanisms that regulate adult astrocyte function are unknown.To ascertain whether NFIA contributes to mature astrocyte function, we generated new transgenic mouse lines that specifically eliminates it in adult astrocytes. Preliminary studies with these mice revealed that astrocytes lacking NFIA exhibit region-specific changes in morphology, that are coupled with impaired Ca2+ activity. These changes in astrocyte function directly impact neuronal physiology, as synaptic activity is impaired and the induction of long term potentiation (LTP) is inhibited. Accordingly, this inhibition of LTP corresponds with deficits in learning and memory behaviors. Together, these observations reveal a novel transcriptional mechanism regulating adult astrocyte function and associated neuronal circuits, while also defining a new role for NFIA in the brain. Therefore, based on the strength of these preliminary data, we propose the following specific aims.
In specific aim 1, we will determine how loss of NFIA influences astrocyte morphology and function across a diverse range of brain regions, over a series of timepoints, post-deletion of NFIA. Functional studies will include assessing astrocyte membrane conductance and calcium responses using genetically encoded GCaMP reporters.
In specific aim 2, we will focus on the hippocampus and determine how loss of NFIA in astrocytes influences neuronal physiology, circuit function, and associated behaviors. These studies will make use of basic physiological studies to assess basal and evoked/plasticity responses in neurons.
In specific aim 3, we have identified a set of candidate NFIA target genes that we will functionally validate and in the second part of this aim will identify NFIA target gene networks in astrocytes, across diverse brain regions to decode region specific vulnerabilities to NFIA loss in the adult brain.
The focal point of this project is to understand how transcription factors regulate the function of astrocytes in the adult brain. Given that astrocyte function is linked to a wide spectrum of neurological disease states, these studies are likely to reveal new mechanisms that can be applied to the understanding and possible treatment of these disorders. The transcription factor that we are studying (Nuclear Factor I-A) has been implicated in both glioma and white matter injury, underscoring the direct connections between these studies and associated disease states.
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