Integrated Multiscale Modeling of the Nervous System: Predicting Changes in Hippocampal Network Activity by a Positive AMPA Receptor Modulator

Abstract

One of the fundamental characteristics of the brain is its hierarchical organization. Scales in both space and time that must be considered when integrating across hierarchies of the nervous system are sufficiently great as to have impeded the development of routine multilevel modeling methodologies. Complex molecular interactions at the level of receptors and channels regulate activity at the level of neurons; interactions between multiple populations of neurons ultimately give rise to complex neural systems function and behavior. This spatial complexity takes place in the context of a composite temporal integration of multiple, different events unfolding at the millisecond, second, minute, hour, and longer time scales. In this study, we present a multiscale modeling methodology that integrates synaptic models into single neuron, and multineuron, network models. We have applied this approach to the specific problem of how changes at the level of kinetic parameters of a receptor-channel model are translated into changes in the temporal firing pattern of a single neuron, and ultimately, changes in the spatiotemporal activity of a network of neurons. These results demonstrate how this powerful methodology can be applied to understand the effects of a given local process within multiple hierarchical levels of the nervous system.

Back Action on Neurotransmitters by Receptor Binding Reveals an Optimal Receptor Density Profile

“…We present the results for one vesicle release in Figure 9A, where it is clear that the current responses from both theoretical models are almost identical, although they have faster rise and decay times than the superimposed experimental results from reference [30]. All parameters for our AMPA receptor model and diffusion algorithm were optimized [19] with respect to experimental results from reference [23], and the differences observed in Figure 9A are likely due to limitations in experimental recording and dendritic integration, whereby membrane capacitance slows the response. Furthermore, the kinetic rate constants have not been optimized to fit the experimental data, which can dramatically affect the time series.…”

“…The parameters for the model given in Table 1 were adapted from the original values used in Robert and Howe [17] to additionally fit the experimental results from Kessler et al [23]. This optimization was presented in Bouteiller et al [19]. We write the coupled rate equations associated with the kinetic schemes as follows: …”

“…We will investigate the temporal characteristics of ligand-receptor interactions due to buffered diffusion as well as its resulting quantitative functional implications on global synaptic AMPA receptor function. We consider a classical receptor kinetic model for the AMPA receptors, which has been described in numerous publications [17][18][19] using a glutamate diffusion profile unaffected by binding (free dif-fusion case). We then determine the dynamics of the receptor-limited diffusion model, this time considering the impact of glutamate binding/unbinding on free glutamate concentration profile in the cleft.…”

A multi-scale computational model for the study of retinal prosthetic stimulation

“…More spatial scales can be integrated as well, including smaller scales down to the molecular level for describing the synapses and channel mechanisms with even higher complexity. It has been shown that small changes at the molecular level can have an impact on the neural-level reaction to electrical activity [12]. Through these modifications, a highly accurate model for studying many different research topics involving circuitry in the retina may be studied.…”

A comparison between direct and indirect measurements of neurotransmitter vesicle release dynamics: A computational study

“…The kinetic models in the EONS platform used for training the functional model include neurotransmitter diffusion [9], the 16 state AMPA receptor model developed by Robert and Howe [10] and the 8 state NMDA receptor model by [11]. For more details on the EONS/RHENOMS synaptic platform please see [12] and [13]. …”