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

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. HighlightsO_LIIt is unknown how non-overlapping ensembles are linked in the hippocampal CA3 area. C_LIO_LIMossy fiber inputs prime CA3 pyramidal cells by enhancing dendritic excitability. C_LIO_LIPerforant pathway (PP) inputs to the primed cells induce synaptic strengthening. C_LIO_LIAt the same time, the high excitability state is restored by PP inputs. C_LIO_LIThis learning rule may play a key role in sequence learning in CA3 network. C_LI