Developing Glutamate Uptake Model for Neuron-Astrocyte Synapse
Seppälä, Saana (2022)
Seppälä, Saana
2022
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
2022-11-22
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202211208479
https://urn.fi/URN:NBN:fi:tuni-202211208479
Tiivistelmä
The two most abundant cell types in the brain are neuronal cells and non-neuronal glial cells. Both cell types can form extensive networks of their own, but they also interact with each other. Recently in the field of neuroscience, glial cells have been recognized to have significantly larger roles in the central nervous system, compared to the previously thought roles in homeostasis and as supporting cells. As an example, glial cells have been shown to participate in sensory information processing and higher brain functions. One specialized subtype of glial cells is astrocytes. Astrocytes have been shown to be closely associated with neuronal synapses and to participate in the regulation of synaptic functions and plasticity. The interactions between neurons and astrocytes in the brain are driven by many complex cellular mechanisms. Such mechanisms include, for example, exocytosis and uptake of transmitters and other molecules.
One important form of interaction between neurons and astrocytes at the synaptic level is glutamate uptake. Glutamate is an excitatory neurotransmitter, released into the synaptic cleft by neurons. Excess glutamate in the synaptic cleft can lead to neurotoxic reaction, such as epileptic seizures, so the glutamate concentration must be carefully modulated. It has been shown that most of the glutamate uptake is carried out by astrocytes. Astrocytes actively control the glutamate dynamics in the synaptic cleft by taking up glutamate through specific glutamate transporters, and releasing it to the extrasynaptic space.
In this thesis work, a previously published and validated synapse model was further developed to incorporate a direct pathway for astrocytic glutamate uptake from the synaptic cleft. The previous model described dynamics in a specific synapse in somatosensory cortex, where evidence of astrocytes modulating synaptic plasticity has previously been found. The new model component for astrocytic glutamate uptake dynamics was developed based on a comprehensive survey and literature search of astrocytic glutamate transporter models. Due to the level of complexity and the biophysical nature of the original synapse model, it was of interest to reconcile whether it is even possible to integrate this mechanism.
The simulation results obtained with the new implementation of the model were promising, since the new model was reasonably fitted to produce results close to those of the original model. The successful integration of the glutamate uptake component made it possible to perform further simulations to study the behavior of the new model. The dynamics and results of the new model are related to the ability of the synapse to learn and modulate sensory information, making the model a viable tool for further research on the role of astrocytic glutamate uptake. It was of importance to introduce a fully replicable model code, thus all new and modified mathematical expressions and implementation details are presented.
One important form of interaction between neurons and astrocytes at the synaptic level is glutamate uptake. Glutamate is an excitatory neurotransmitter, released into the synaptic cleft by neurons. Excess glutamate in the synaptic cleft can lead to neurotoxic reaction, such as epileptic seizures, so the glutamate concentration must be carefully modulated. It has been shown that most of the glutamate uptake is carried out by astrocytes. Astrocytes actively control the glutamate dynamics in the synaptic cleft by taking up glutamate through specific glutamate transporters, and releasing it to the extrasynaptic space.
In this thesis work, a previously published and validated synapse model was further developed to incorporate a direct pathway for astrocytic glutamate uptake from the synaptic cleft. The previous model described dynamics in a specific synapse in somatosensory cortex, where evidence of astrocytes modulating synaptic plasticity has previously been found. The new model component for astrocytic glutamate uptake dynamics was developed based on a comprehensive survey and literature search of astrocytic glutamate transporter models. Due to the level of complexity and the biophysical nature of the original synapse model, it was of interest to reconcile whether it is even possible to integrate this mechanism.
The simulation results obtained with the new implementation of the model were promising, since the new model was reasonably fitted to produce results close to those of the original model. The successful integration of the glutamate uptake component made it possible to perform further simulations to study the behavior of the new model. The dynamics and results of the new model are related to the ability of the synapse to learn and modulate sensory information, making the model a viable tool for further research on the role of astrocytic glutamate uptake. It was of importance to introduce a fully replicable model code, thus all new and modified mathematical expressions and implementation details are presented.