The hippocampal CA3 area implements sequence learning of discontinuous episodes.

Sequence learning requires linking memories of adjacent events by sharing ensemble cells. It remains unclear how the hippocampal CA3 links non-overlapping memory representations in sequence learning. High frequency mossy fiber inputs to a CA3 pyramidal cell downregulate Kv1.2 in distal apical dendrites to enhance its voltage response to perforant pathway inputs, and the high excitability is restored by subsequent perforant pathway inputs. Consistent with this notion, we found that CA3 ensemble cells activated by a novel context display high excitability, and their high excitability state is restored by re-activation during the second visit to a similar but distinct context. Computational modeling suggests that this bi-directional excitability regulation enables ordered association of orthogonal neuronal ensembles representing sequential events. Supporting this, CA3-specific Kcna2 + /- mice, which lack synaptic regulation of excitability, exhibited impaired sequence learning. These findings reveal the synaptic mechanisms by which the CA3 network encodes sequential memories.