Thermodynamic-based astrocytic glutamate transport model and implications for synaptic excitability

Research output: Contribution to conferenceAbstract

Abstract

The kinetics of neurotransmitters is of great importance to physiological and patho-physiological studies. In particular, the efficient removal of excitatory neurotransmitter glutamate by astrocytes is of great interest within the study of epileptic seizure generation. Without effective clearance, glutamate acts as a hyperexcitability agent, repeatedly depolarising nearby neurons through NMDA and AMPA-mediated currents. The authors previously developed a thermodynamic-based computational model for astrocytic glutamate transporters, EAAT2, illustrating a reliance of effective glutamate clearance on co-transporter substrate regulation and regulated intracellular glutamate levels. In this abstract, we demonstrate the clearance capability of EAAT2 where intracellular glutamate basal concentrations are increased due, perhaps, to disrupted metabolism and in response to increasing presynaptic firing frequencies. The model details astrocytic regulation of K+ and Na+ concentrations by Na+/K+-ATPase, glutamate-mediated astrocytic [Ca2+] oscillations and highly responsive NCX transport. In Fig. 1 our model shows for lower presynaptic firing (<20 Hz) delayed, although successful, glutamate clearance due to reduced ionic concentration gradients is sufficient to significantly increase post-synaptic firing activity. However, this correlation is less pronounced at higher presynaptic frequencies due to accumulation of glutamate in the synaptic space, resulting in the saturation of ionotropic glutamate receptors across each paradigm. This outcome has significant implications for post synaptic neuronal hyper-excitability which is presented further in the poster.

Conference

Conference11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience
CountryGermany
CityBerlin
Period7/07/1811/07/18
Internet address

Fingerprint

thermodynamics
metabolism
oscillation
saturation
substrate
kinetics
firing
regulation
removal
seizure

Cite this

Flanagan, B., McDaid, LJ., Wong-Lin, K., Harkin, J., & Wade, J. (Accepted/In press). Thermodynamic-based astrocytic glutamate transport model and implications for synaptic excitability. Abstract from 11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience, Berlin, Germany.
Flanagan, Bronac ; McDaid, LJ ; Wong-Lin, KongFatt ; Harkin, Jim ; Wade, John. / Thermodynamic-based astrocytic glutamate transport model and implications for synaptic excitability. Abstract from 11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience, Berlin, Germany.
@conference{7ca267d5c8714419a6bd6aed8c889221,
title = "Thermodynamic-based astrocytic glutamate transport model and implications for synaptic excitability",
abstract = "The kinetics of neurotransmitters is of great importance to physiological and patho-physiological studies. In particular, the efficient removal of excitatory neurotransmitter glutamate by astrocytes is of great interest within the study of epileptic seizure generation. Without effective clearance, glutamate acts as a hyperexcitability agent, repeatedly depolarising nearby neurons through NMDA and AMPA-mediated currents. The authors previously developed a thermodynamic-based computational model for astrocytic glutamate transporters, EAAT2, illustrating a reliance of effective glutamate clearance on co-transporter substrate regulation and regulated intracellular glutamate levels. In this abstract, we demonstrate the clearance capability of EAAT2 where intracellular glutamate basal concentrations are increased due, perhaps, to disrupted metabolism and in response to increasing presynaptic firing frequencies. The model details astrocytic regulation of K+ and Na+ concentrations by Na+/K+-ATPase, glutamate-mediated astrocytic [Ca2+] oscillations and highly responsive NCX transport. In Fig. 1 our model shows for lower presynaptic firing (<20 Hz) delayed, although successful, glutamate clearance due to reduced ionic concentration gradients is sufficient to significantly increase post-synaptic firing activity. However, this correlation is less pronounced at higher presynaptic frequencies due to accumulation of glutamate in the synaptic space, resulting in the saturation of ionotropic glutamate receptors across each paradigm. This outcome has significant implications for post synaptic neuronal hyper-excitability which is presented further in the poster.",
author = "Bronac Flanagan and LJ McDaid and KongFatt Wong-Lin and Jim Harkin and John Wade",
year = "2018",
month = "4",
day = "9",
language = "English",
note = "11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience ; Conference date: 07-07-2018 Through 11-07-2018",
url = "https://www.fens.org/Meetings/Forum/",

}

Flanagan, B, McDaid, LJ, Wong-Lin, K, Harkin, J & Wade, J 2018, 'Thermodynamic-based astrocytic glutamate transport model and implications for synaptic excitability' 11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience, Berlin, Germany, 7/07/18 - 11/07/18, .

Thermodynamic-based astrocytic glutamate transport model and implications for synaptic excitability. / Flanagan, Bronac; McDaid, LJ; Wong-Lin, KongFatt; Harkin, Jim; Wade, John.

2018. Abstract from 11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience, Berlin, Germany.

Research output: Contribution to conferenceAbstract

TY - CONF

T1 - Thermodynamic-based astrocytic glutamate transport model and implications for synaptic excitability

AU - Flanagan, Bronac

AU - McDaid, LJ

AU - Wong-Lin, KongFatt

AU - Harkin, Jim

AU - Wade, John

PY - 2018/4/9

Y1 - 2018/4/9

N2 - The kinetics of neurotransmitters is of great importance to physiological and patho-physiological studies. In particular, the efficient removal of excitatory neurotransmitter glutamate by astrocytes is of great interest within the study of epileptic seizure generation. Without effective clearance, glutamate acts as a hyperexcitability agent, repeatedly depolarising nearby neurons through NMDA and AMPA-mediated currents. The authors previously developed a thermodynamic-based computational model for astrocytic glutamate transporters, EAAT2, illustrating a reliance of effective glutamate clearance on co-transporter substrate regulation and regulated intracellular glutamate levels. In this abstract, we demonstrate the clearance capability of EAAT2 where intracellular glutamate basal concentrations are increased due, perhaps, to disrupted metabolism and in response to increasing presynaptic firing frequencies. The model details astrocytic regulation of K+ and Na+ concentrations by Na+/K+-ATPase, glutamate-mediated astrocytic [Ca2+] oscillations and highly responsive NCX transport. In Fig. 1 our model shows for lower presynaptic firing (<20 Hz) delayed, although successful, glutamate clearance due to reduced ionic concentration gradients is sufficient to significantly increase post-synaptic firing activity. However, this correlation is less pronounced at higher presynaptic frequencies due to accumulation of glutamate in the synaptic space, resulting in the saturation of ionotropic glutamate receptors across each paradigm. This outcome has significant implications for post synaptic neuronal hyper-excitability which is presented further in the poster.

AB - The kinetics of neurotransmitters is of great importance to physiological and patho-physiological studies. In particular, the efficient removal of excitatory neurotransmitter glutamate by astrocytes is of great interest within the study of epileptic seizure generation. Without effective clearance, glutamate acts as a hyperexcitability agent, repeatedly depolarising nearby neurons through NMDA and AMPA-mediated currents. The authors previously developed a thermodynamic-based computational model for astrocytic glutamate transporters, EAAT2, illustrating a reliance of effective glutamate clearance on co-transporter substrate regulation and regulated intracellular glutamate levels. In this abstract, we demonstrate the clearance capability of EAAT2 where intracellular glutamate basal concentrations are increased due, perhaps, to disrupted metabolism and in response to increasing presynaptic firing frequencies. The model details astrocytic regulation of K+ and Na+ concentrations by Na+/K+-ATPase, glutamate-mediated astrocytic [Ca2+] oscillations and highly responsive NCX transport. In Fig. 1 our model shows for lower presynaptic firing (<20 Hz) delayed, although successful, glutamate clearance due to reduced ionic concentration gradients is sufficient to significantly increase post-synaptic firing activity. However, this correlation is less pronounced at higher presynaptic frequencies due to accumulation of glutamate in the synaptic space, resulting in the saturation of ionotropic glutamate receptors across each paradigm. This outcome has significant implications for post synaptic neuronal hyper-excitability which is presented further in the poster.

M3 - Abstract

ER -

Flanagan B, McDaid LJ, Wong-Lin K, Harkin J, Wade J. Thermodynamic-based astrocytic glutamate transport model and implications for synaptic excitability. 2018. Abstract from 11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience, Berlin, Germany.