Chronic activation of astrocytic Gq GPCR 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 Gq protein-coupled receptors (Gq GPCRs) present on their surface. Astrocytic Gq GPCR activation induces Ca2+ release from internal stores, leading to intracellular Ca2+ elevations. There is emerging evidence supporting that astrocytic Gq GPCR Ca2+ elevations are upregulated and dysregulated in neurodegenerative diseases and are thought to play an important role in the pathogenesis of such diseases. Furthermore, astrocytic Gq GPCR Ca2+-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 Gq GPCR Ca2+ 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 Gq GPCR Ca2+ 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 Gq GPCR Ca2+ 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 Gq 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.