Functional Domains of Neuron-to-Astrocyte Gq GPCR Communication

The physiological role of astrocytic Gq-protein coupled receptors (Gq GPCRs) has now drawn more attention in the field of neuroscience, as it is now clear that astrocytes sense neuronal signals through activation of their Gq GPCRs. Astrocytes are thus considered excitable and their role in synaptic transmission is under intense investigation. Interestingly, in basal conditions without any user-evoked stimulation, astrocytes exhibit spontaneous Gq GPCR activity driven by mechanisms that still remain mysterious. Understanding the mechanisms underlying these astrocytic Gq GPCR signaling domains in physiological conditions will certainly benefit our knowledge regarding neuron-to-astrocyte communication. Therefore, the main goal of this dissertation is to study the underlying mechanisms of astrocytic Gq GPCR signaling domains in two parts: 1) To identify the factors governing spontaneous astrocytic Gq GPCR activity, and 2) To identify the lowest threshold of neuronal action potential-mediated synaptic transmission capable of evoking an astrocytic Gq GPCR response, and then to determine if the response occurs as a microdomain or a whole-cell event. In Chapter 2, we demonstrate that spontaneous astrocytic Gq GPCR signaling domains are driven by mechanisms unrelated to action potential-triggered neurotransmitter release, but are dependent on spontaneous miniature neurotransmitter release. It also appears that multiple types of astrocytic Gq GPCRs play essential roles in the generation of spontaneous Gq GPCR activity. In Chapter 3, our results suggest that astrocytes respond to neuronal afferent stimulation at intensities much lower than previously described. Moreover, the evoked Gq GPCR domains are qualitatively different from the spontaneous ones. Consistent with the findings from Chapter 2, the evoked events appear to involve multiple types of astrocytic Gq GPCRs. These data suggest that astrocytes respond to neuronal activity in a manner much more sensitive than previously thought. We also explored the role of beta-Arrestin2 in regulating two forms of synaptic plasticity-long-term potentiation (LTP) and long-term depression (LTD). In Chapter 4, we report normal LTP, but a markedly impaired LTD in beta-Arrestin2 knockout mice, suggesting a novel role of beta-Arrestin2 in cellular mechanisms of learning and memory. This finding could potentially provide a base for developing treatments for dementia-related disorders such as Alzheimer's disease