Neuron-glia signaling is important for neural development and functions. This signaling may be regulated by neuronal activity and undergo modification similar to long-term potentiation (LTP) of neuronal synapses, a hallmark of neuronal plasticity. We found that tetanic stimulation of Schaffer collaterals (Sc) in the hippocampus that induced LTP in neurons also resulted in LTP-like persistent elevation of Sc-evoked slow depolarization in perisynaptic astrocytes. The elevated slow depolarization in astrocytes was abolished by NMDA receptor antagonist and K⁺ channel inhibitors, but not by Ca²⁺ chelator BAPTA loaded in the recorded astrocytes, suggesting involvement of an increased extracellular K⁺ accumulation accompanying LTP of neuronal synapses. The increased K⁺ accumulation and astrocyte depolarization following LTP induction may reduce the efficiency of glial glutamate transporters, which may contribute to the enhanced synaptic efficacy. The neuronal activity-induced persistent enhancement of neuron-glia signaling may thus have important physiological relevance.