Astrocytic Glutamate Transporters: Physiology and Simulations
Ylihärsilä, Sofia (2023)
Ylihärsilä, Sofia
2023
Bioteknologian ja biolääketieteen tekniikan maisteriohjelma - Master's Programme in Biotechnology and Biomedical Engineering
Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology
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Hyväksymispäivämäärä
2023-05-26
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202305165828
https://urn.fi/URN:NBN:fi:tuni-202305165828
Tiivistelmä
Astrocytes have many roles in the central nervous system, ranging from homeostatic regulation to information processing in the brain. One function of astrocytes is the uptake of glutamate from the synaptic cleft using glutamate transporters (excitatory amino acid transporters). The uptake of glutamate is a critical process, which enables correct neurotransmission and prevents excitotoxicity and neurodegenerative conditions.
In this work, the goal was to study glutamate transporters in detail using a computational single-cell astrocyte model. A six-state cyclic kinetic scheme of the transporter, with reversible reactions and realistic kinetic constants, was incorporated into ASTRO simulation environment. In addition to the transporter properties, the possible association of a calcium signal with the glutamate transport process was studied by adding a sodium-calcium exchanger model which was available in ModelDB database.
In the simulations, an increased glutamate concentration in the extracellular space activates the glutamate transporters. The response of the model is examined in terms of concentration changes of different ions and current amplitudes and durations. The simulations showed a fast uptake of extracellular glutamate, which in the case of 0.5 mM extracellular glutamate occurred in 5 ms. The current generated by the transporter was measured in a voltage clamp simulation of ASTRO tool, which showed an amplitude of 0.25 nA and a duration of about 50 ms. Regarding the calcium signal, the sodium-calcium exchanger was found to reverse its function and thus transport calcium into the cell when glutamate transporters were active, creating a detectable calcium signal. However, the physiological relevance of this signal is not yet known, and more studies are needed to address this question.
The response of the model to different extracellular glutamate concentrations was also studied, and the result was that doubling the glutamate concentration increased the uptake time by 700%. Furthermore, the model was sensitive to different transporter amounts. A 30% reduction in transporter amount led to glutamate uptake time increasing by 300%. This would be an interesting research question for experimental studies, because transporter trafficking to the membrane could be one mechanism that gets disturbed in brain disorders and diseases, leading to decreased transporter amounts, and resulting in excess glutamate at the synaptic cleft.
In this work, the goal was to study glutamate transporters in detail using a computational single-cell astrocyte model. A six-state cyclic kinetic scheme of the transporter, with reversible reactions and realistic kinetic constants, was incorporated into ASTRO simulation environment. In addition to the transporter properties, the possible association of a calcium signal with the glutamate transport process was studied by adding a sodium-calcium exchanger model which was available in ModelDB database.
In the simulations, an increased glutamate concentration in the extracellular space activates the glutamate transporters. The response of the model is examined in terms of concentration changes of different ions and current amplitudes and durations. The simulations showed a fast uptake of extracellular glutamate, which in the case of 0.5 mM extracellular glutamate occurred in 5 ms. The current generated by the transporter was measured in a voltage clamp simulation of ASTRO tool, which showed an amplitude of 0.25 nA and a duration of about 50 ms. Regarding the calcium signal, the sodium-calcium exchanger was found to reverse its function and thus transport calcium into the cell when glutamate transporters were active, creating a detectable calcium signal. However, the physiological relevance of this signal is not yet known, and more studies are needed to address this question.
The response of the model to different extracellular glutamate concentrations was also studied, and the result was that doubling the glutamate concentration increased the uptake time by 700%. Furthermore, the model was sensitive to different transporter amounts. A 30% reduction in transporter amount led to glutamate uptake time increasing by 300%. This would be an interesting research question for experimental studies, because transporter trafficking to the membrane could be one mechanism that gets disturbed in brain disorders and diseases, leading to decreased transporter amounts, and resulting in excess glutamate at the synaptic cleft.