Genetically-Encoded, Non-Invasive and Wireless Modulation of Calcium Dynamics in Astrocytes With Spatiotemporal Precision and Depth

Abstract Astrocytes are the most abundant cell types in the brain and have long been thought as primarily passive support cells. Studies in the past two decades leveraging modern techniques have revealed crucial roles for astrocytes in neuronal circuit assembly, synaptic function and behavior. Aberrant astrocytic function is implicated in neuropsychiatric and neurodegenerative diseases, and astrocytes hold great promises as novel therapeutic targets for improving treatment efficacy. Despite this progress, a deeper mechanistic understanding of astrocytes' causative and correlative roles in operating neural circuitry and their contribution to behavior is still lacking. This knowledge gap is largely due to the lack of technologies to effectively manipulate astrocyte activity with cell-type and temporal precision. The physiological hallmark of astrocytes is their complex spatiotemporal patterns of intracellular and intercellular calcium signaling crucial to their bidirectional interaction with neurons. The objective of this project is to develop a non-invasive, wireless and genetically encoded actuator to modulate astrocytic activity with cell-type and temporal precision in vivo. Our approach, named FeRIC (Ferritin iron Redistribution to Ion Channels), combines the use of radiofrequency (RF) waves and ion channels to control membrane ion permeability non-invasively and wirelessly. The FeRIC technique utilizes RF waves to activate membrane proteins that are coupled to the endogenous cellular iron storage protein ferritin. Our preliminary studies have demonstrated the feasibility of FeRIC-mediated RF stimulation to modulate calcium activities in astrocytes and astrocytic networks that resembles those observed under physiological conditions. Further, FeRIC-mediated RF stimulation of astrocytes has been able to elicit neurotransmitter release and evoke action potentials in connected neurons. We aim to develop a set of molecular tools and characterize their abilities 1) to modulate global calcium signaling in astrocytes, 2) to modulate microdomain calcium activities in astrocytes and 3) to modulate astrocyte-neuron interactions at the tripartite synapses in vivo. If successful, the project will develop a non-invasive and genetically encoded molecular tool to modulate astrocytic activity with cell-type and temporal precision. We will elucidate the biophysical underpinnings of the mechanism. The project will have a broad impact to the study of the roles of astrocytes in health and disease.