Chronic activation of astrocytic GqGPCR signaling has causal effects on visual LTP formation: implications for neurodegenerative diseases

Astrocytes are the most abundant glial cells in the central nervous system and interact with other cell types, including neurons and microglia, via G q protein-coupled receptors (G q GPCRs) present on their surface. Astrocytic G q GPCR activation induces Ca 2+ release from internal stores, leading to intracellular Ca 2+ elevations. There is emerging evidence supporting that astrocytic G q GPCR Ca 2+ elevations are upregulated and dysregulated in neurodegenerative diseases and are thought to play an important role in the pathogenesis of such diseases. Furthermore, astrocytic G q GPCR Ca 2+ -dependent release of neuroactive or inflammatory molecules from astrocytes may occur in the early steps of the stress/inflammatory process in the diseased brain. In addition, low grade and chronic brain inflammation is involved in the etiology of neurodegenerative diseases. We hypothesized that chronic activation of astrocytic G q GPCR Ca 2+ signaling leads to an altered production of glutamate or pro-inflammatory factors from astrocytes, and consequent deficits in synaptic transmission, long-term potentiation (LTP), and memory formation. To test this hypothesis, we used an AAV-based chemogenetic tool to selectively activate astrocyte G q GPCR Ca 2+ signaling combined with in vivo electrophysiology, immunohistochemistry, and biochemistry. Using the mouse primary visual cortex (V1) as a model system, we found that chronically increased astrocytic G q GPCR Ca 2+ signaling leads to a decrease in LTP of visual-evoked potentials. Such LTP impairment was associated with microglial reactive phenotype - displaying a hyper-ramified and proliferative state - as well as a decrease in the number of interleukin 33 (IL-33)-expressing astrocytes. Our study is the first to have shown that chronic astrocytic G q GPCR activation is sufficient to alter visual LTP and induce astrocyte-to-microglia communication, possibly through and IL-33 pathway in the adult brain. Because GPCRs are important drug targets, our study could have relevant therapeutic implications in the treatment of some neurodegenerative diseases.