A biophysical model of synaptic transmission during energy deprivation
Hannah van Susteren (EEMCS MIA), Hil G.E. Meijer (EEMCS MIA), Michel J.A.M. van Putte n (TNW - CNPH)
Abstract
Cerebral ischemia is a condition in which blood flow and oxygen supply are restricted. Clinical consequences range from moderate disabilities to patient death. The initial consequence of reduced oxygen supply is malfunction of synaptic transmission, interrupting neuronal communication. Many subprocesses have been studied experimentally, but their interplay during synaptic transmission failure remains unclear. We have constructed a detailed biophysical model to explore the different stages of synaptic failure.
We extend the model of (Kalia et al., 2021) and consider a presynaptic neuron and astrocyte confined in a finite extracellular space (ECS). An oxygen bath surrounds the ECS so that oxygen can diffuse to the ECS and sustain various active processes. To model synaptic transmission, we combine calcium-dependent glutamate release and uptake with a novel implementation of the complete glutamate-glutamine cycle. We simulate different severities of ischemia by reducing the bath oxygen level for various time intervals.
We simulate synaptic transmission during and after moderate and severe ischemia. Our model faithfully reproduces baseline physiological behaviour. During ischemia, we observe reduced glutamate release due to impaired calcium signaling. The energy-dependent glutamine synthesis is impaired, leading to a defective glutamate-glutamine cycle. After moderate ischemia, the presynaptic neuron recovers and regains excitability while synaptic transmission remains disturbed, as observed experimentally (Bolay et al., 2002; Hofmeijer & van Putten, 2012). After severe ischemia, the neuron has reached an irreversible pathological state with toxic levels of glutamate in the ECS. In conclusion, we simulate the interplay of multiple stages of synaptic transmission failure during and after ischemia using a single model.
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Hofmeijer, J., & van Putten, M. J. (2012). Ischemic cerebral damage: an appraisal of synaptic failure. Stroke
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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. https://doi.org/10.1371/journal.pcbi.1009019