(620e) Spatiotemporal Dopaminergic Modulation of Schaffer Collateral-CA1 Plasticity: A Computational Modeling Approach

Dopamine acts as a critical neuromodulator involved in significantly modulating the hippocampal Schaffer collateral CA1 pyramidal (SC-CA1Py) synaptic plasticity in a dose-dependent manner and thus plays an essential role in shaping hippocampal-dependent learning and memory by regulating the strength of this synapse. Experimentally, it has been shown in a few limited experimental studies that the timing of the activation of the dopamine receptors (D1/D5R) by the pharmacological D1/D5R agonist SKF 38393 relative to high-frequency-stimulation / low-frequency-stimulation (HFS/LFS) of the Schaffer collateral synapse leads to different modulations of the induced long-term-potentiation/long-term-depression (LTP/LTD) of the SC-CA1Py synapse. Although these limited experiments provide insight into few extreme timings of D1/D5R activation relative to the HFS/LFS stimulation, it is not clear how much the LTP/LTD modulation will occur if one activates the D1/D5 receptors at times other than these extreme timings, such as 30 minutes before and after the HFS/LFS stimulation or at different D1/D5 agonist concentrations. Here, we attempt to provide essential insights to fill in the gaps of our current understanding on the D1/D5 receptors mediated modulation of SC-CA1py synaptic long-term potentiation/depression (LTP/LTD) by developing a computational modeling framework, for the first time, that predicts the D1/D5 receptor-mediated spatiotemporal modulation of the HFS/LFS induced LTP/LTD at the electrophysiological level.

We developed a set of phenomenological models to describe the temporal dose-dependent effect of dopamine D1/D5 receptors agonist on the HFS/LFS induced LTP/LTD of the SC-CA1Py synapse using published electrophysiological data from hippocampal CA1 slice experiments. We used an experimentally validated single compartmental biophysiological model in a Hodgkin-Huxley formalism to represent the CA1Py neuron dynamics. The synaptic dynamics, as well as the dynamics of high/low-frequency stimulation (HFS/LFS), induced LTP/LTD of SC-CA1Py synapse were described using published phenomenological models of SC-CA1Py synaptic dynamics and LTP/LTD. We used an approximate Bayesian computation method based on sequential Monte Carlo scheme to estimate the unknown model parameters using the available electrophysiological data from the literature.

We used our model to predict experimentally observed temporal effects of D1/D5R activation by SKF 38393 with different timing relative to HFS/LFS and SKF 38393 concentrations. The predictions from our model show a good agreement, both qualitatively and quantitatively, with the experimental results published in the literature. Based on the results from our model, we conclude that the temporal modulation of the HFS/LFS induced LTP/LTD of the SC-CA1Py synapse by SKF 38393 strongly depends on both the timing of the administration of SKF 38393 relative to the HFS/LFS as well as the concentration SKF 38393. Furthermore, the temporal modulation of the HFS/LFS induced LTP/LTD of the SC-CA1Py synapse by SKF 38393 is independent of the HFS/LFS protocol.