Ionic Homeostasis at the Perisynaptic Cradle

Abstract

It is now known that astrocytes, the major class of glial cells, act as a third synaptic terminal and respond to neurotransmitters by releasing gliotransmitters. Structurally, astrocytes function primarily through their processes which are frequently extremely fine (<50 nm) with a large surface-to-volume ratio. They are rarely studied in live tissue, as they are not directly accessible to electrophysiology and are smaller than microscopic resolution. For this reason this thesis proposes that in order to advance our understanding of interactions between an astrocyte and nearby synapses, a computational modelling approach is essential.

The underlying hypothesis put forward in this thesis is that in thin astrocyte process, fixed negative charges existing in inner process membrane will be the dominant ionic conduction in the process cytoplasm. Specifically, it is proposed that these negative charges give rise to potential wells and therefore ions must hop from well to well as they move along the thin astrocyte process. Consequently this low conductance pathway serves to semi-isolate the astrocytic perisynaptic cradle (PsC) from the astrocytic main body.

A computational model of the PsC is developed which includes ionic hopping in the process cytoplasm. It made 4 key predictions:
1. The model gave results which agreed with experimental observation in that both Na⁺  and K⁺ microdomains form at the PsC, and that the mechanism underpinning this behaviour was the low conductance pathway between the PsC and the astrocyte soma: the low conductance pathway is a direct result of ion retention in the potential wells.2. Additionally, a slow decay of Na⁺ was also observed in our simulation after a period of glutamate simulation which is in strong agreement with experimental observations. The pathological implications of microdomain formation during neuronal excitation are also discussed.3. The model also predicted that the K⁺ microdomain provides the driving force for the return of K⁺ to the extracellular space for uptake by the neuron, thereby preventing K⁺ undershoot. This observation is in direct contrast to the prevailing view of K⁺ clearance, and may point towards a new mechanism for K⁺ homeostasis at the PsC.4. Furthermore, the model predicted that a Ca²⁺ microdomain can form due to reversal of the NCX extruder and the implications of this is significant in that a local source of Ca²⁺ is produced in the absence of the endoplasmic reticulum.

Date of Award	Jul 2019
Original language	English
Sponsors	Department for the Economy
Supervisor	Liam Mc Daid (Supervisor), Jim Harkin (Supervisor), John Wade (Supervisor) & Kongfatt Wong-Lin (Supervisor)