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Dopamine plays a critical role in modulating the long-term synaptic plasticity of the hippocampal Schaffer collateral-CA1 pyramidal neuron synapses (SC-CA1), a widely accepted cellular model of learning and memory. Limited results from hippocampal slice experiments over the last four decades have shown that the timing of the activation of dopamine D1/D5 receptors relative to a high/low-frequency stimulation (HFS/LFS) in SC-CA1 synapses regulates the modulation of HFS/LFS-induced long-term potentiation/depression (LTP/LTD) in these synapses. However, the existing literature lacks a complete picture of how various concentrations of D1/D5 agonists and the relative timing between the activation of D1/D5 receptors and LTP/LTD induction by HFS/LFS, affect the spatiotemporal modulation of SC-CA1 synaptic dynamics. In this paper, we have developed a computational model, a first of its kind, to make quantitative predictions of the temporal dose-dependent modulation of the HFS/LFS induced LTP/LTD in SC-CA1 synapses by various D1/D5 agonists. Our model combines the biochemical effects with the electrical effects at the electrophysiological level. We have estimated the model parameters from the published electrophysiological data, available from diverse hippocampal CA1 slice experiments, in a Bayesian framework. Our modeling results demonstrate the capability of our model in making quantitative predictions of the available experimental results under diverse HFS/LFS protocols. The predictions from our model show a strong nonlinear dependency of the modulated LTP/LTD by D1/D5 agonists on the relative timing between the activated D1/D5 receptors and the HFS/LFS protocol and the applied concentration of D1/D5 agonists. [ABSTRACT FROM AUTHOR]

Under sustained input current of increasing strength neurons eventually stop firing, entering a depolarization block. This is a robust effect that is not usually explored in experiments or explicitly implemented or tested in models. However, the range of current strength needed for a depolarization block could be easily reached with a random background activity of only a few hundred excitatory synapses. Depolarization block may thus be an important property of neurons that should be better characterized in experiments and explicitly taken into account in models at all implementation scales. Here we analyze the spiking dynamics of CA1 pyramidal neuron models using the same set of ionic currents on both an accurate morphological reconstruction and on its reduction to a single-compartment. The results show the specific ion channel properties and kinetics that are needed to reproduce the experimental findings, and how their interplay can drastically modulate the neuronal dynamics and the input current range leading to a depolarization block. We suggest that this can be one of the rate-limiting mechanisms protecting a CA1 neuron from excessive spiking activity. [ABSTRACT FROM AUTHOR]