Computational modelling of ionostasis at the tripartite synapse

Abstract

Astrocytes, a type of glial cell in the brain, have traditionally been considered passive cells that provide support and housekeeping duties for the energy hungry, electrically excitable neuronal cells. Although there is broad consensus that astrocytes provide many supporting roles for neurons like structural support and homeostasis, recent experimental evidence shows that astrocytes can also have an active role in information transfer in the neuronal network through their influence over neuronal synapses. Astrocytes are known to cover up to 80% of neuronal synapses in the hippocampus and their spongiform morphology and the small scale of peripheral astrocyte branches/leaflets make studying these cells experimentally in vivo extremely difficult. Therefore, this thesis uses computational modelling to study the dynamic signalling interactions between astrocytes and the neuronal synapses they ensheath.

The hypothesis presented here is that astrocyte branches can integrate local signals generated from the astroglial response to neuronal activity and can respond with a calcium transient signal in their branches. A literature review is carried out separately for the biological and computational modelling literature, highlighting the state-of-the-art and current gaps in our knowledge. A new biophysical model for astrocyte-neuron signalling is presented which captures how cradle motility effects potassium and glutamate clearance at synaptic junctions: the model proposes that NMDA activity is the dominant source of potassium at synaptic junctions. Additionally, the model proposes that calcium uptake by the cradle may be the catalyst for leaflet motility and that astrocytes lose their ability to form calcium microdomains in the cradle when the cradle fully enwraps a neuronal synapse. Results from simulating various neuronal signalling regimes also show that astrocytes can detect a higher occurrence of neuronal activity and can respond with a large calcium release from the endoplasmic reticulum. Overall, these results provide strong support for the hypothesis.

Date of Award	May 2023
Original language	English
Supervisor	Liam Mc Daid (Supervisor), John Wade (Supervisor) & Jim Harkin (Supervisor)