A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed to
provide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessity
of a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.
LanguageEnglish
Article number14(4): e1006040
Pages1-25
Number of pages25
JournalPLoS Computational Biology
Volume14
Issue number4
Early online date16 Apr 2018
DOIs
Publication statusE-pub ahead of print - 16 Apr 2018

Fingerprint

Glutamic Acid
Amino Acid Transport System X-AG
Astrocytes
Down-Regulation
Glutamate-Ammonia Ligase
Temporal Lobe Epilepsy
Extracellular Space
Brain Diseases
Thermodynamics
Synaptic Transmission
Synapses
Epilepsy
Pathology
Membranes

Keywords

  • Astrocyte
  • Glutamate
  • EAAT
  • Gliotransmission
  • Glutaminesynthetase
  • tripartite-synapse
  • computational model

Cite this

@article{c6b9971258ac474486b6a29a1392224d,
title = "A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability",
abstract = "The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed toprovide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessityof a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.",
keywords = "Astrocyte, Glutamate, EAAT, Gliotransmission, Glutaminesynthetase, tripartite-synapse, computational model",
author = "Bronac Flanagan and LJ McDaid and John Wade and KongFatt Wong-Lin and Jim Harkin",
year = "2018",
month = "4",
day = "16",
doi = "10.1371/journal.pcbi.1006040",
language = "English",
volume = "14",
pages = "1--25",
journal = "PLoS Computational Biology",
issn = "1553-734X",
number = "4",

}

A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability. / Flanagan, Bronac; McDaid, LJ; Wade, John; Wong-Lin, KongFatt; Harkin, Jim.

In: PLoS Computational Biology, Vol. 14, No. 4, 14(4): e1006040, 16.04.2018, p. 1-25.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability

AU - Flanagan, Bronac

AU - McDaid, LJ

AU - Wade, John

AU - Wong-Lin, KongFatt

AU - Harkin, Jim

PY - 2018/4/16

Y1 - 2018/4/16

N2 - The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed toprovide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessityof a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.

AB - The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed toprovide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessityof a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.

KW - Astrocyte

KW - Glutamate

KW - EAAT

KW - Gliotransmission

KW - Glutaminesynthetase

KW - tripartite-synapse

KW - computational model

U2 - 10.1371/journal.pcbi.1006040

DO - 10.1371/journal.pcbi.1006040

M3 - Article

VL - 14

SP - 1

EP - 25

JO - PLoS Computational Biology

T2 - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-734X

IS - 4

M1 - 14(4): e1006040

ER -