Abstract

Summary Mental experiences can become long-term memories if the hippocampal activity patterns that encode them are broadcast during network oscillations. The activity of inhibitory neurons is essential for generating these neural oscillations, but molecular control of this dynamic process during learning remains unknown. Here, we show that hippocampal oscillatory strength positively correlates with excitatory monosynaptic drive onto inhibitory neurons (E→I) in freely behaving mice. To establish a causal relationship between them, we identified γCaMKII as the long-sought mediator of long-term potentiation for E→I synapses (LTP E→I ), which enabled the genetic manipulation of experience-dependent E→I synaptic input/plasticity. Deleting γCaMKII in parvalbumin interneurons selectively eliminated LTP E→I and disrupted experience-driven strengthening in theta and gamma rhythmicity. Behaviorally, this manipulation impaired long-term memory, for which the kinase activity of γCaMKII was required. Taken together, our data suggest that E→I synaptic plasticity, exemplified by LTP E→I , plays a gatekeeping role in tuning experience-dependent brain rhythms and mnemonic function.