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.
|Publication status||Accepted/In press - 9 Apr 2018|
|Event||11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience - Berlin, Germany|
Duration: 7 Jul 2018 → 11 Jul 2018
|Conference||11th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience|
|Period||7/07/18 → 11/07/18|
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.