Neuronal activity drives pathway-specific depolarization of astrocyte distal processes

Astrocytes are glial cells that interact with neuronal synapses via their distal processes, where they remove glutamate and potassium (K ⁺ ) from the extracellular space following neuronal activity. Astrocyte clearance of both glutamate and K ⁺ is voltage-dependent, but astrocyte membrane potential (V _m ) has been thought to be largely invariant. As a result, these voltage-dependencies have not been considered relevant to astrocyte function. Using genetically encoded voltage indicators enabling the measurement of V _m at distal astrocyte processes (DAPs), we report large, rapid, focal, and pathway-specific depolarizations in DAPs during neuronal activity. These activity-dependent astrocyte depolarizations are driven by action potential-mediated presynaptic K ⁺ efflux and electrogenic glutamate transporters. We find that DAP depolarization inhibits astrocyte glutamate clearance during neuronal activity, enhancing neuronal activation by glutamate. This represents a novel class of sub-cellular astrocyte membrane dynamics and a new form of astrocyte-neuron interaction.