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bioRxiv · 10.1101/2025.10.01.676159

Ca2+ Plateau Potentials Reflect Cross-Theta Cortico-Hippocampal Input Dynamics and Acetylcholine for Rapid Formation of Efficient Place-Cell Code

Wang, H.-Y.·Hsu, Y.-C.·Huang, H.-P.·Chen, C.-T.·Huang, X.-B.·Wang, C.-T.·Naud, R.·Hsu, C.-L.
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Abstract

A central tenet of Systems Neuroscience lies in an understanding of memory and behavior through learning rules, but synaptic plasticity has rarely been shown to create functional single-neuron code in a causal and biophysically rooted manner. Behavioral Time-Scale Synaptic Plasticity (BTSP), identified in vivo, holds a great potential for explaining instantaneous hippocampal selectivity emergence by long-term potentiation (LTP), yet the cellular and endogenous mechanisms are unknown, impeding broader conceptualization of this novel rule for its algorithmic, systems-level and theoretical implications. Here, we addressed this gap by in-vivo, ex-vivo, in-silico and computational approaches to seek neurophysiologically inspired protocols for synaptically evoking Ca2+ plateau potentials and inducing potentiation in the CA1. We found induction of BTSP-LTP is best explained by a theta-oscillation-paced, gradually developed cellular state being supported with precisely timed weak ramping inputs. Remarkably, the previously presumed one-shot LTP for in-vivo place-field formation is possible under the influence of muscarinic activation. Through modeling, the notion of acetylcholine-gated BTSP gave rise to a computational advantage for low-interference continual learning. We further demonstrated that biophysics of Transient Receptor Potential (TRPM) and NMDA receptor (NMDAR) channels powerfully shapes the cross-theta dynamics underlying BTSP. These results which cover pre-, post-synaptic and neuromodulatory factors and their timing suggest fundamental principles for graded plateau potentials and hippocampal LTP induction. Overall, our work dissects cellular mechanisms potentially important for a prominent in-vivo hippocampal plasticity phenomenon, and offers a biological basis for framing BTSP as an input-dynamics-aware, neuromodulation-tuned synaptic algorithm.

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Wang, H.-Y., Hsu, Y.-C., Huang, H.-P., Chen, C.-T., Huang, X.-B., Wang, C.-T., Naud, R., Hsu, C.-L.. 2025-10-02. Ca2+ Plateau Potentials Reflect Cross-Theta Cortico-Hippocampal Input Dynamics and Acetylcholine for Rapid Formation of Efficient Place-Cell Code. https://doi.org/10.1101/2025.10.01.676159

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