Neuronal activity drives pathway-specific depolarization of peripheral astrocyte 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) is thought to be largely invariant. As a result, these voltage dependencies have not been considered relevant to astrocyte function. Using genetically encoded voltage indicators to enable the measurement of V_m at peripheral astrocyte processes (PAPs) in mice, we report large, rapid, focal and pathway-specific depolarizations in PAPs during neuronal activity. These activity-dependent astrocyte depolarizations are driven by action potential-mediated presynaptic K⁺ efflux and electrogenic glutamate transporters. We find that PAP depolarization inhibits astrocyte glutamate clearance during neuronal activity, enhancing neuronal activation by glutamate. This represents a novel class of subcellular astrocyte membrane dynamics and a new form of astrocyte–neuron interaction.