A biophysical model of synaptic transmission during energy deprivation

Cerebral ischemia is a condition in which blood flow and oxygen supply are restricted, resulting in compromised neuronal function. Clinical consequences range from moderate disabilities to patient death. Reduced oxygen supply affects two essential energy-dependent processes, i.e., ion homeostasis and synaptic transmission. Synaptic transmission includes the energy-dependent glutamate-glutamine cycle, which enables glutamate recycling via the astrocyte. Although there is a considerable amount of experimental data on synaptic transmission failure, the interplay of all different stages of the effects of ischemia on synaptic transmission is not yet fully known. To address this interplay, we have constructed a detailed biophysical model that includes the first implementation of the complete glutamate-glutamine cycle. Our model enables us to investigate the malfunction of synaptic transmission during ischemia and during recovery.

We elaborate on the model of (Kalia et al., 2021) and consider a presynaptic neuron and astrocyte confined in a finite extracellular space (ECS). The ECS is surrounded by an oxygen bath that allows oxygen diffusion between the bath and the ECS. To maintain ion homeostasis, the transmembrane ion fluxes are counteracted by ion transporters, such as the energy-dependent sodium-potassium ATPase (NKA). To model glutamate endocytosis and exocytosis, we combine calcium-dependent glutamate release with uptake by the excitatory amino acid transporter. To complete glutamate recycling, the glutamate-glutamine cycle converts astrocytic glutamate into glutamine in an energy-dependent manner. Subsequently, glutamine is transported back to the neuron, where it is converted to glutamate. In the model, water transport is based on differences in osmotic pressure, which can lead to cell swelling. To simulate ischemia, we lower the oxygen concentration in the bath. We simulate different severities of ischemia by changing the duration of reduced oxygen and the level of oxygen.

Our model faithfully reproduces baseline physiological behaviour. We analyze synaptic transmission during and after moderate and severe ischemia. During ischemia, we observe reduced glutamate exocytosis due to impaired calcium signaling. In addition, the glutamate-glutamine cycle is disturbed due to malfunction of energy-dependent glutamine synthesis. After moderate ischemia, the presynaptic neuron recovers and regains excitability while synaptic transmission remains disturbed due to impaired presynaptic exocytosis, as has been observed experimentally (Bolay et al., 2002; Hofmeijer & van Putten, 2012). After severe ischemia, ion homeostasis is disturbed, and the cell volume has increased. Impaired glutamate uptake together with excessive exocytosis has led to toxic levels of glutamate in the ECS. The neuron has reached an irreversible pathological state in which it is not excitable anymore. In conclusion, we simulate the interplay of multiple stages and levels of synaptic transmission failure during and after ischemia using a single model.

Bolay, H., Gürsoy-Ozdemir, Y., Sara, Y., Onur, R., Can, A., & Dalkara, T. (2002). Persistent defect in transmitter release and synapsin phosphorylation in cerebral cortex after transient moderate ischemic injury. Stroke, 33(5), 1369-1375.
Hofmeijer, J., & van Putten, M. J. (2012). Ischemic cerebral damage: an appraisal of synaptic failure. Stroke, 43(2), 607-615.
Kalia, M., Meijer, H. G. E., van Gils, S. A., van Putten, M. J. A. M., & Rose, C. R. (2021). Ion dynamics at the energy-deprived tripartite synapse. PLOS Computational Biology, 17(6), e1009019.