Inhibitory plasticity supports replay generalization in the hippocampus

Memory consolidation assimilates recent experiences into long-term memory. This process requires the replay of learned sequences, although the content of these sequences remains controversial. Recent work has shown that the statistics of replay deviate from those of experience: stimuli that are experientially salient may be either recruited or suppressed from sharp-wave ripples. In this study, we found that this phenomenon can be explained parsimoniously and biologically plausibly by a Hebbian spike-time-dependent plasticity rule at inhibitory synapses. Using models at three levels of abstraction-leaky integrate-and-fire, biophysically detailed and abstract binary-we show that this rule enables efficient generalization, and we make specific predictions about the consequences of intact and perturbed inhibitory dynamics for network dynamics and cognition. Finally, we use optogenetics to artificially implant non-generalizable representations into the network in awake behaving mice, and we find that these representations also accumulate inhibition during sharp-wave ripples, experimentally validating a major prediction of our model. Our work outlines a potential direct link between the synaptic and cognitive levels of memory consolidation, with implications for both normal learning and neurological disease.