| Description |
Astrocytes are glial cells that make up 50% of brain volume, with each one wrapping around thousands of synapses. In the presence of neuronal activity, astrocytes exhibit calcium transients, hinting that these cells may be playing an active role in regulating brain activity. Evidence suggests that astrocytes are involved in synaptic plasticity, buffering of extracellular ions, and several neurological disorders. However, the underlying mechanisms of their calcium signals and how they lead to these functions remain unclear. We begin by examining the data collected by our collaborators, in which they evoked calcium responses via brief stimulant applications. Even in this controlled setup, calcium transients exhibit a vast range of amplitudes and durations, with some presenting multiple peaks after one stimulus. We develop a computational model that captures the diversity of responses and use it to propose a classification system for the types of transients observed. Further, we demonstrate that calcium activity in an astrocyte can influence neuronal activity by affecting extracellular ion concentrations. We show that variability in the time course of the signaling molecule IP3 is enough to create the variability of the observed calcium responses. We investigate the source of this variability through a novel stochastic process in which n particles are diffusing and interacting with receptors. We derive mathematical results related to this process by considering our system in several ways: as a spatial diffusion process with recharging receptors; as a continuous-time Markov process approximating the original system; and as a system of ODEs in a mean-field approximation. We prove that by accounting for the finite recharge time that occurs between binding events, the expected number of captured particles has an upper-bound of order log(n). Thus, only a small number of molecules are binding to receptors, leading to more variability than previously expected. Further, we find that through ensheathment (how tight an astrocyte wraps a synapse), astrocytes can tune the time course of neurotransmitters in the synaptic cleft, and thus the strength of neuronal connections. Lastly, we discuss preliminary work on incorporating these results into a new type of neuronal network that includes the effects of astrocytes. |
