Incorporating the Effects of Synaptic Ensheathment in Neuronal Networks: A Multi-scale Investigation

University Of Utah, Salt Lake City UT

Investigators

Abstract

This project will develop a mathematical framework to study the role of synapse wrapping by astrocytes, a type of brain cells, with the aim of efficient and accurate astrocyte representation in neuronal networks. Astrocytes have multiple arms, called processes, and are linked with important brain functions but their involvement is not well-understood. Often astrocytes wrap processes around synapses, the contacts between neurons. The number of wrapped synapses and wrapping tightness changes in diseases such as epilepsy. The role of such differences is not yet understood and will be investigated in this project. The problem is challenging and multi-scale: astrocyte wrapping acts at the scale of individual, but it affects neuronal networks involving thousands of neurons. The effects of wrapping will first be studied at the individual synapse level by developing mathematical theory and detailed biological models. Next, the essential features of connections altered by wrapping will be extracted and included in neuronal network models. The effective network-level representation of astrocyte ensheathment will be as simple as possible to aid implementation in a variety of networks and minimize computing costs, but will preserve the essential biological features derived from detailed models. The resulting hybrid networks will reveal the effects of ensheathment conditions corresponding to different brain areas and disease states. The project will involve graduate and undergraduate trainees and will be disseminated through research presentations, training courses, K-12 and public presentations. Synaptic ensheathment is ubiquitous in the brain but not ordinarily included in models as a property of network structure. Thus, this study explores a novel aspect of a more general problem of network structure-function relationship, central in modern neuroscience. Expected findings will contribute to understanding the complex interactions between the two major brain cell types. To this end, computational and mathematical analysis will be used to study the role of synaptic ensheathment at different spatial and temporal scales. First, the influence of degree of synaptic ensheathment on synaptic function will be investigated at the spatiotemporal scale of molecules and receptors to determine how ensheathment affects the (random) number of molecules reaching the post-synaptic and astrocytic receptors as a function of time, the resulting astrocyte calcium response, and excitability of the postsynaptic cell. This will involve extending mathematical theories of diffusion with switching boundaries to spatially-extended initial conditions and developing a method to quantify roles of individual parameters in controlling the system behavior. These detailed, biologically-realistic studies will inform how synaptic and post-synaptic properties are determined by the level of ensheathment. Next, in an excitatory-inhibitory network, each synapse will be endowed with its own ensheathment parameters and the resulting firing rate and synchronization properties will be determined based on the distribution of ensheathment properties. This will be done both in simulations and by extending network activity coherence measures to include synaptic ensheathment. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.