A computational model of dopaminergic modulation of hippocampal Schaffer collateral-CA1 long-term plasticity

Abstract

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 D1/D5 agonists activating cAMP-mediating biochemical pathways. 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 as well as the applied concentration of D1/D5 agonists. Particularly, our model predicts that D1/D5 agonists could significantly boost the LTP induced by weak HFS if the agonist is applied much before the HFS protocol. Furthermore, our model predicts that specific D1/D5 agonists can convert the LFS-induced LTD in SC-CA1 synapses to LTP if D1/D5 receptors are activated before the applied LFS protocol. Author summary Dopamine, a reward neuromodulator, plays an essential role in shaping hippocampal-dependent learning and memory of behavioral tasks. Limited experimental studies have revealed that pharmacological agents of dopaminergic receptors can significantly modulate the electrically-induced long-term potentiation/depression (LTP/LTD) of the hippocampal Schaffer collateral CA1 pyramidal (SC-CA1) synapses, a cellular model of learning and memory, in a time and dose dependent manner. However, exploring the effect of the parameter space of various concentration levels of the applied pharmacological agent as well as the frequency-specific characteristics of the high (low) frequency stimulation (H(L)FS) protocol on the dopaminergic receptors’ mediated spatiotemporal modulation of LTP/LTD is a combinatorically challenging problem which is both expensive and time-consuming to address in experiments alone. Here, we develop a multi-timescale computational modeling framework to address this question. Our model integrates the slow biochemical dynamics and the fast-electrical dynamics of the CA1 pyramidal neuron and makes quantitative predictions of the experimentally observed modulation of H(L)FS-induced LTP/LTD in SC-CA1 synapses by dopaminergic (D1/D5) receptors agonists. Our modeling results complement the experimental findings and show specific predictions on the potential role of dopamine in strengthening weak synapses.