Input-specific bi-directional regulation of CA3 pyramidal cell excitability: its implications in sequence learning

Neuronal excitability is a key determinant for recruitment of a neuron to an ensemble. High-frequency mossy fiber (MF) inputs induce a prolonged increase in the excitability of a CA3 pyramidal cell (called long-term potentiation of intrinsic excitability, LTP-IE), thereby weak perforant pathway (PP) inputs can induce long-term potentiation at PP synapses (PP-LTP). However, sustained hyperexcitability is detrimental, and a mechanism to reverse this primed state is necessary. Here, we show that burst firings of CA3 pyramidal cells elicited by PP or recurrent synaptic inputs reverse the MF-induced LTP-IE. Moreover, the high-frequency PP inputs to MF-primed CA3 pyramidal cells induced not only PP-LTP but also restored the high excitability state. Labeling a neuronal ensemble using c-fos promoter in animals exposed to a novel context, we found most CA3 ensemble cells exhibited increased excitability, indicative of LTP-IE. Moreover, when the animals experienced novel contexts twice with an interval, a substantial subset of putative twice-activated CA3 ensemble cells exhibited reduced excitability, implying depotentiation of LTP-IE. We developed an in silico model based on these experimental results and found that MF-induced LTP-IE and its depotentiation are critical for association of orthogonal neuronal ensembles representing temporally discontiguous events. Highlights It is unknown how non-overlapping ensembles are linked in the hippocampal CA3 area. Mossy fiber inputs prime CA3 pyramidal cells by enhancing dendritic excitability. Perforant pathway (PP) inputs to the primed cells induce synaptic strengthening. At the same time, the high excitability state is restored by PP inputs. This learning rule may play a key role in sequence learning in CA3 network.