Astrocytes gate long-term potentiation in hippocampal interneurons

Long-term potentiation is involved in physiological processes such as 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 synapses onto excitatory neurons (LTP_E→E), the mechanism of LTP on excitatory glutamatergic synapses 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→Iremain incompletely defined., We studied the role of astrocytes in regulating LTP_E→Iin the hippocampal CA1 region and their impact on cognitive function using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics and behavior tests. We showed that LTP_E→Iin the stratum oriens of hippocampal CA1 is astrocyte independent. However, in the stratum radiatum, synaptically released endocannabinoids increase astrocyte Ca²⁺via type-1 cannabinoid receptors, stimulate D-serine release, and potentiate excitatory synaptic transmission on inhibitory neurons through the activation of (N-methyl-D-aspartate) NMDA receptors. We also revealed that chemogenetic activation of astrocytes is sufficient for inducing NMDA-dependentde novoLTP_E→Iin the stratum radiatum of the hippocampus. Furthermore, we found that disrupting LTP_E→Iby knocking down γCaMKII in interneurons of the 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→Ipathway.