Astrocytes comprise the major glial cell type in the brain and regulate numerous brain functions including neural development, clearance of neurotransmitters, and regulation of blood flow. Recent evidence indicates that astrocytes also play direct roles in regulating neuronal excitability and synaptic transmission by secreting a variety of neuroactive factors including proinflammatory cytokines. These proinflammatory cytokines evoke a vast array of effects on neurons as well as glia including alterations in Ca2+ signaling and synaptic transmission, which are implicated in brain pathologies such as neuropathic pain and Alzheimer’s Disease. However, the checkpoints that regulate astrocyte-mediated production and release of inflammatory mediators are poorly understood. Previous studies have suggested that Ca2+-dependent transcriptional and secretory processes play a major role in mediating the production and release of proinflammatory mediators. However, the Ca2+ channels that drive these processes in astrocytes are unclear. We have recently shown that store-operated Ca2+ release-activated Ca2+ (CRAC) channels are a major mechanism for neurotransmitter-evoked Ca2+ signals in astrocytes and their opening stimulates the release of gliotransmitters via regulated exocytosis. We further show that activation of CRAC channels in astrocytes strongly stimulates the transcription and secretion of a wide range of proinflammatory cytokines and chemokines. Based on this evidence, we hypothesize that CRAC channels are essential regulators of astrocyte-mediated neuroinflammation. We propose three specific aims to test this hypothesis: 1) Define the role of CRAC channels for the inflammatory output of astrocytes, 2) Determine the effects of CRAC channel-mediated secretion of proinflammatory mediators on neuronal Ca2+ signaling and synaptic transmission, and 3) examine the in vivo relevance of CRAC channel-mediated inflammatory cytokine production from astrocytes in a model of neuropathic pain. We will approach these questions using a multidisciplinary approach that combines genetic knockouts of CRAC channel proteins with in-depth molecular and biochemical assays, focal glutamate uncaging, slice electrophysiology, and behavioral analysis. Collectively, results from these studies will advance our understanding of the physiological role of CRAC channels for regulating astrocyte-mediated neuroinflammation and aid the quest for developing new astrocyte-targeted therapies for pathological diseases affecting brain function.
|Effective start/end date||7/1/21 → 6/30/26|
- National Institute of Neurological Disorders and Stroke (2R01NS057499-14A1)
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