CA3–CA3 recurrent excitatory synapses are thought to play a key role in memory storage and pattern completion. Whether the plasticity properties of these synapses are consistent with their proposed network functions remains unclear. Here, we examine the properties of spike timing-dependent plasticity (STDP) at CA3–CA3 synapses. Low-frequency pairing of excitatory postsynaptic potentials (EPSPs) and action potentials (APs) induces long-term potentiation (LTP), independent of temporal order. The STDP curve is symmetric and broad (half-width ∼150 ms). Consistent with these STDP induction properties, AP–EPSP sequences lead to supralinear summation of spine [Ca2+] transients. Furthermore, afterdepolarizations (ADPs) following APs efficiently propagate into dendrites of CA3 pyramidal neurons, and EPSPs summate with dendritic ADPs. In autoassociative network models, storage and recall are more robust with symmetric than with asymmetric STDP rules. Thus, a specialized STDP induction rule allows reliable storage and recall of information in the hippocampal CA3 network.

CA3 pyramidal neurons are important for memory formation and pattern completion in the hippocampal network. It is generally thought that proximal synapses from the mossy fibers activate these neurons most efficiently, whereas distal inputs from the perforant path have a weaker modulatory influence. We used confocally targeted patch-clamp recording from dendrites and axons to map the activation of rat CA3 pyramidal neurons at the subcellular level. Our results reveal two distinct dendritic domains. In the proximal domain, action potentials initiated in the axon backpropagate actively with large amplitude and fast time course. In the distal domain, Na + channel-mediated dendritic spikes are efficiently initiated by waveforms mimicking synaptic events. CA3 pyramidal neuron dendrites showed a high Na + -to-K + conductance density ratio, providing ideal conditions for active backpropagation and dendritic spike initiation. Dendritic spikes may enhance the computational power of CA3 pyramidal neurons in the hippocampal network.CA3 pyramidal neurons in the hippocampal network are critical for spatial information processing and memory 1-5 . These neurons receive three different glutamatergic inputs. Proximal mossy fiber synapses activate CA3 cells efficiently, acting as 'conditional detonators' 6,7 . Commissural/associational synapses between CA3 cells are thought to store memories by spike timing-dependent plasticity, but whether backpropagated action potentials efficiently invade the postsynaptic dendrites in CA3 pyramidal neurons is unclear [8][9][10] . Distal perforant path synapses from the entorhinal cortex may relay information about context 2 , but how synaptic signals are conducted to the soma via the long dendritic cable has not been resolved. Recent results have suggested that most entorhinal cortex layer 2 pyramidal neurons are grid cells 11 , indicating that perforant path inputs may signal precise spatiotemporal information. How this information is processed by CA3 pyramidal cell dendrites remains unclear.To understand both the induction rules of synaptic plasticity and the efficacy of distal inputs in CA3 pyramidal neurons, knowledge about the properties of the dendrites of these neurons is essential. Highly detailed information is available about the dendrites of layer 5 pyramidal cells in the neocortex and CA1 pyramidal neurons in the hippocampus 12-15 (reviewed by ref. 16). In contrast, both the difficulty of maintaining CA3 pyramidal cells in in vitro slice preparations and the small caliber of the dendritic processes of these cells have prevented a detailed analysis by direct recordings. Recent experiments using glutamate uncaging have

Key pointsr We investigated the cellular mechanisms underlying mossy fibre-induced heterosynaptic long-term potentiation of perforant path (PP) inputs to CA3 pyramidal cells.r Here we show that this heterosynaptic potentiation is mediated by downregulation of Kv1.2 channels.r The downregulation of Kv1.2 preferentially enhanced PP-evoked EPSPs which occur at distal apical dendrites.r Such enhancement of PP-EPSPs required activation of dendritic Na + channels, and its threshold was lowered by downregulation of Kv1.2.r Our results may provide new insights into the long-standing question of how mossy fibre inputs constrain the CA3 network to sparsely represent direct cortical inputs.Abstract A short high frequency stimulation of mossy fibres (MFs) induces long-term potentiation (LTP) of direct cortical or perforant path (PP) synaptic inputs in hippocampal CA3 pyramidal cells (CA3-PCs). However, the cellular mechanism underlying this heterosynaptic modulation remains elusive. Previously, we reported that repetitive somatic firing at 10 Hz downregulates Kv1.2 in the CA3-PCs. Here, we show that MF inputs induce similar somatic firing and downregulation of Kv1.2 in the CA3-PCs. The effect of Kv1.2 downregulation was specific to PP synaptic inputs that arrive at distal apical dendrites. We found that the somatodendritic expression of Kv1.2 is polarized to distal apical dendrites. Compartmental simulations based on this finding suggested that passive normalization of synaptic inputs and polarized distributions of dendritic ionic channels may facilitate the activation of dendritic Na + channels preferentially at distal apical dendrites. Indeed, partial block of dendritic Na + channels using 10 nM tetrodotoxin brought back the enhanced PP-evoked excitatory postsynaptic potentials (PP-EPSPs) to the baseline level. These results indicate that activity-dependent downregulation of Kv1.2 in CA3-PCs mediates MF-induced heterosynaptic LTP of PP-EPSPs by facilitating activation of Na + channels at distal apical dendrites.J. H. Hyun and K. Eom authors contributed equally to this study.

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