New Proteomic and Genome Engineering Approaches to Decipher Astrocyte Function at Synapses

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ABSTRACT Astrocytes are the most abundant glial cells in the human brain. Interactions of astrocytes with synapses via thin perisynaptic astrocytic processes are critical for proper synaptic connectivity and function. Each mouse astrocyte sends out an extensive array of processes that are estimated to contact over 100,000 synapses. The number of astrocytes and the extent of their interactions with synapses have increased throughout evolution, indicating a close link between astrocytes and cognition. Moreover, emerging evidence suggests that dysfunction of astrocyte-synapse interactions contributes to a variety of brain disorders. In contrast to neuronal synaptic structures, however, we are largely blind to the molecular composition and mechanisms of the astrocytic perisynaptic structures. Moreover, there is currently very little understanding of how mutations that disrupt astrocyte-synapse interactions lead to synaptic pathologies. This is in large part because, unlike neuronal synaptic structures, it has not been possible to purify and identify proteins enriched at subcellular regions of astrocytes. In this project, we will develop and utilize innovative proteomic and genome editing approaches to solve these problems, revealing the proteins and inner workings of astrocyte processes that associate with and modulate synapses. We anticipate these data will provide a new and unparalleled molecular framework for future studies on astrocyte- neuron interactions.