Abstract Long-term potentiation is involved in physiological process like learning and memory, motor learning and sensory processing, and pathological conditions such as addiction. In contrast to the extensive studies on the mechanism of long-term potentiation on excitatory glutamatergic synapse onto excitatory neurons (LTP E→E ), the mechanism of LTP on excitatory glutamatergic synapse onto inhibitory neurons (LTP E→I ) remains largely unknown. In the central nervous system, astrocytes play an important role in regulating synaptic activity and participate in the process of LTP E→E , but their functions in LTP E→I remain incompletely defined. Using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics and behavior tests, we studied the role of astrocytes in regulating LTP E→I in the hippocampal CA1 region and their impact on cognitive function. We show that LTP E→I in stratum oriens of hippocampal CA1 is astrocyte independent. However, in the stratum radiatum, synaptically released endocannabinoids increases astrocyte Ca 2+ via type-1 cannabinoid receptors, stimulates D-serine release, and potentiate excitatory synaptic transmission on inhibitory neuron through the activation of (N-methyl-D-aspartate) NMDA receptors. We also revealed that chemogentic activation of astrocytes is sufficient to induce NMDA-dependent de novo LTP E→I in the stratum radiatum of hippocampus. Furthermore, we found that disrupt LTP E→I by knockdwon γCaMKII in interneurons of stratum radiatum resulted in dramatic memory impairment. Our findings suggest that astrocytes release D-serine, which activates NMDA receptors to regulate LTP E→I , and that cognitive function is intricately linked with the proper functioning of this LTP E→I pathway.
