Shaping Neuronal Network Activity by Presynaptic Mechanisms

Neuronal microcircuits generate oscillatory activity, which has been linked to basic functions such as sleep, learning and sensorimotor gating. Although synaptic release processes are well known for their ability to shape the interaction between neurons in microcircuits, most computational models do not simulate the synaptic transmission process directly and hence cannot explain how changes in synaptic parameters alter neuronal network activity. In this paper, we present a novel neuronal network model that incorporates presynaptic release mechanisms, such as vesicle pool dynamics and calcium-dependent release probability, to model the spontaneous activity of neuronal networks. The model, which is based on modified leaky integrate-and-fire neurons, generates spontaneous network activity patterns, which are similar to experimental data and robust under changes in the model's primary gain parameters such as excitatory postsynaptic potential and connectivity ratio. Furthermore, it reliably recreates experimental findings and provides mechanistic explanations for data obtained from microelectrode array recordings, such as network burst termination and the effects of pharmacological and genetic manipulations. The model demonstrates how elevated asynchronous release, but not spontaneous release, synchronizes neuronal network activity and reveals that asynchronous release enhances utilization of the recycling vesicle pool to induce the network effect. The model further predicts a positive correlation between vesicle priming at the single-neuron level and burst frequency at the network level; this prediction is supported by experimental findings. Thus, the model is utilized to reveal how synaptic release processes at the neuronal level govern activity patterns and synchronization at the network level.
Author Summary The activity of neuronal networks underlies basic neural functions such as sleep, learning and sensorimotor gating. Computational models of neuronal networks have been developed to capture the complexity of the network activity and predict how neuronal networks generate spontaneous activity. However, most computational models do not simulate the intricate synaptic release process that governs the interaction between neurons and has been shown to significantly impact neuronal network activity and animal behavior, learning and memory. Our paper demonstrates the importance of simulating the elaborate synaptic release process to understand how neuronal networks generate spontaneous activity and respond to manipulations of the release process. The model provides mechanistic explanations and predictions for experimental pharmacological and genetic manipulations. Thus, the model presents a novel computational platform to understand how mechanistic changes in the synaptic release process modulate network oscillatory activity that might impact basic neural functions.