Accumulating evidence over the past few decades has revealed that astrocytes, a type of glial cell in the brain, are more involved in active brain communication than previously thought. In addition to serving a multitude of homeostatic roles in the brain, astrocytes also participate in bidirectional communication with neurons, a phenomenon that has important consequences for brain function. One way in which astrocytes communicate with neurons is through calcium-induced release of their own signaling molecules, termed gliotransmitters. A well-studied mechanism of calcium signaling in astrocytes is G protein-coupled receptor (GPCR) signaling, particularly Gq GPCR signaling. A less-studied calcium signaling pathway in astrocytes is through Gi/o GPCR activation. In neurons, activation of Gq GPCRs and Gi/o GPCRs leads to cellular excitation and inhibition, respectively. Whether the same effects occur in astrocytes, and the consequences of such signaling, is the focus of experiments in Chapter Two. I used both an endogenous and chemogenetic approach (i.e. DREADDs) to characterize the functional consequences of Gq and Gi/o GPCR signaling pathways in neurons and astrocytes. I found that activation of Gq GPCRs led to excitation in both neurons and astrocytes. In contrast, Gi/o GPCR activation led to cellular inhibition in neurons, but activation in astrocytes. Both Gq and Gi/o GPCR activation in astrocytes stimulated the release of glutamate that increased neuronal excitability. These results add additional complexity to neural communication in the brain and suggest that inhibitory signaling in particular may be a particular property of neurons. Chapter Three delves further into the consequences of GPCR signaling in astrocytes and whether it is involved in mediating long-term plasticity. While Chapter Two shows the consequences of activating astrocyte GPCRs exogenously, Chapter Three investigates the consequences of activating astrocyte GPCRs synaptically. In particular, I investigate the role of astrocytes in mediating long-term depression (LTD) at a subset of synapses in the dorsolateral striatum. Despite extensive research into neuronal circuitry in the striatum, little work has been done in elucidating the role of astrocytes in striatal function. I show that astrocytes respond to high-frequency stimulation-induced LTD through mGluR5, a type of glutamate Gq-coupled GPCR. In return, astrocytes release the gliotransmitter ATP, which is necessary for inducing LTD at corticostriatal synapses. Through both a loss of function and gain of function approach, I demonstrate that astrocytes are an integral participant of striatal plasticity. Taken together, these studies add to the growing evidence that astrocytes play active roles in information processing in the brain, a dogmatic shift in the previously-held notion that astrocytes serve strictly support functions.
University of Minnesota Ph.D. dissertation. April 2019. Major: Neuroscience. Advisor: Alfonso Araque. 1 computer file (PDF); vii, 115 pages.
G Protein Signaling In Astrocytes Regulates Neuronal Excitability And Synaptic Plasticity.
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