Temporal Coding rather than Circuit Wiring allows Hippocampal CA3 Neurons to Dynamically Distinguish Different Cortical Inputs

Abstract Memory relies on associating and indexing multimodal information. How does this occur within single neurons? The hippocampus integrates multisensory information from medial (MEC) and lateral (LEC) entorhinal cortices to form environmental representations 1-6 , yet their synaptic dynamics, circuit organization, and integrative functions remain elusive. Contrary to canonical models emphasizing anatomical and functional segregation, our dual-color optogenetic 7 circuit mapping revealed that both MEC and LEC inputs converge on virtually every CA3 pyramidal neuron and exhibit similar input-output functions and modulation via GABAergic microcircuitry. Divergence occurs in their frequency-dependent short-term plasticity. With increasing frequencies, facilitating LEC-evoked responses undergo synaptic depression, whereas MEC-evoked responses continue facilitating. In vivo, MEC-originating dentate spikes fire CA3 more than LEC, likely due to their distinct temporal relationship with oscillatory activity. Our findings support that hippocampal area CA3 processes region-specific information from MEC and LEC via temporal coding, rather than hard-wired circuit organization, at both single-neuron and network levels.