The Functional Implications of GPCR Signaling in Aging Astrocytes

Astrocytes are a key component of the central nervous system (CNS). Changes in astrocyte morphology and function can impact neurotransmission, blood-brain barrier integrity, and neuroimmune responses. Previous research indicates that glial fibrillary acid protein (GFAP), a common marker used to assess astrocyte activation, is up-regulated as a function of aging.

Many studies examining astrocytes in aging have focused on how they may exacerbate neuroimmune responses and contribute to neurodegeneration. For example, Clarke and colleagues discovered increased proinflammatory but decreased neurotrophic cytokine gene expression in aged astrocytes. This proinflammatory milieu is thought to be an underlying mechanism that increases neurodegeneration with aging. However, glutamatergic tone is decreased in aging, especially in Alzheimer’s patients.

With the development of novel chemogenetic tools, it is now possible to specifically target receptor signaling in astrocytes and determine their roles in various behaviors and pathophysiological conditions. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) under a GFAP promoter, it is possible to elucidate the physiologic and pathologic role of the g-protein coupled receptors (GPCRs) in astrocytes within discrete brain regions.

Because aging can result in abnormal gains in astrocyte function, these studies seek to examine the hypothesis that age-related changes in the hippocampus can be acutely ameliorated by Gq-activation of astrocytes. This project will examine how Gq-signaling in astrocytes affects glutamatergic tone using an HPLC to examine microdialysate samples. The researchers believe that acute Gq activation will restore age-related deficits in glutamate. Because excess glutamate can also cause damage, they will also examine whether chronic GFAP-DREADD activation contributes to neurodegeneration using fluoro-jade C and proinflammatory cytokines using ELISAs. Finally, the behavioral outcomes of these manipulations will be determined using the hippocampal-dependent memory task, novel object recognition.