P333 Synaptic transmission during ischemia and recovery: a biophysical model including the complete glutamate-glutamine cycle
Hannah van Susteren1, Christine R. Rose2, Hil G.E. Meijer1,Michel J.A.M. van Putten3,4
1Department of Applied Mathematics, University of Twente, Enschede, the Netherlands 2Institute of Neurobiology, Heinrich Heine University, Düsseldorf, Germany 3Clinical Neurophysiology group, department of Science and Technology,University of Twente, Enschede, the Netherlands 4MedischSpectrum Twente, Enschede, the Netherlands
Email:h.vansusteren@utwente.nl Introduction
Cerebral ischemia is a condition in which blood flow and oxygen supply are restricted. Consequences range from synaptic transmission failure to (ir)reversible neuronal damage [1,2]. However, theinterplay of all the different effects of ischemia on synaptic transmission remains unknown. Excitatory synaptictransmission relies on the energy-dependent glutamate-glutamine (GG) cycle, which enables glutamate recycling via the astrocyte.We have constructed a detailed biophysical model that includes the first implementation of the complete GG cycle. Our model enables us to investigate the malfunction of synaptic transmission during ischemia and during recovery.
Methods We extend the model in [3] and consider a presynaptic neuron and astrocyte in a finite extracellular space (ECS), surrounded by an oxygen bath as a proxy for energy supply (Fig. 1A). We consider sodium, potassium, chloride and calcium ion fluxes with corresponding channels and transporters such as the sodium-potassium ATPase. To model synaptic transmission, we combine calcium-dependent glutamate release with uptake by the excitatory amino acid transporter and the GG cycle. This cycle includes glutamine synthesis, glutamine transport and glutamate synthesis. We simulate ischemia by lowering the oxygen concentration in the bath. Furthermore, we simulate candidate recovery mechanisms involved in the recovery of physiological dynamics. Results We simulate severe ischemia by blocking energy supply for five minutes. In this scenario, the neuron enters a depolarization block (Fig. 1B). Repeated glutamate release and changes in ion concentrations result in toxic levels of glutamate in the ECS (Fig. 1C). The GG cycle is impaired due to malfunction of energy-dependent glutamine synthesis. Once energy supply is restored, the neuron remains depolarized and synaptic transmission disrupted. A candidate recovery mechanism is the blockade of the neuronal transient sodium channel. As a result, ion gradients recover, and glutamate clearance is restored. Electrical stimulation generates action potentials and physiological glutamate release, demonstrating full recovery of synaptic transmission. Discussion With our computational model that includes the first implementation of the GG cycle, we can simulate neuronal and astrocytic dynamics during ischemia and recovery. An important finding is that extreme glutamate accumulation is caused by ionic imbalances, and not only by excessive glutamate release. Furthermore, the GG cycle is disrupted due to impaired glutamine synthesis. In conclusion, our detailed model provides insight into the causes of excitatory synaptic transmission failure and suggestions for potential recovery mechanisms.
Figure 1. Figure 1: (A) Schematic overview of the model. (B) Membrane potentials and (C) extracellular glutamate during oxygen deprivation (grey area), sodium block (yellow area) and stimulation (dashed line). Acknowledgements This study was supported by the funds from the Deutsche Forschungsgemeinschaft (DFG), FOR2795 ‘Synapses under stress’. References 1.https://doi.org/10.1016/j.neuropharm.2021.108557 2.https://doi.org/10.3389/fncel.2021.637784 3.https://doi.org/10.1371/journal.pcbi.1009019
