bioRxiv2021
The anatomical and functional organization of neurons and astrocytes at tripartite synapses is essential for reliable neurotransmission, which critically depends on ATP. In low energy conditions, synaptic transmission fails, accompanied by a breakdown of ion gradients, changes in membrane potentials and cell swelling. The resulting cellular damage and cell death are causal to the often devastating consequences of an ischemic stroke. The severity of ischemic damage depends on the age and the brain region in which a stroke occurs, but the reasons for this differential vulnerability are far from understood. In the present study, we address this question by developing a comprehensive biophysical model of a glutamatergic synapse to identify key determinants of synaptic failure during energy deprivation. Our model is based on fundamental biophysical principles, includes dynamics of the most relevant ions, i.e., Na+, K+, Ca2+, Cl- and glutamate, and is calibrated with experimental data. It confirms the critical role of the Na+/K+-ATPase in maintaining ion gradients, membrane potentials and cell volumes. Our simulations demonstrate that the system exhibits two stable states, one physiological and one pathological. During energy deprivation, the physiological state may disappear, forcing a transit to the pathological state, which can be reverted when blocking voltage-gated Na+ and K+ channels. Our model predicts that the transition to the pathological state is favoured if the extracellular space fraction is small. A reduction in the extracellular space volume fraction, as, e.g. observed with ageing, will thus promote the brains susceptibility to ischemic damage. Our work provides new insights into the brains ability to recover from energy deprivation, with translational relevance for diagnosis and treatment of ischemic strokes. Author summaryThe brain consumes energy to keep ion concentrations at normal working conditions. In the case of energy deprivation (ED), e.g., during a stroke, synaptic communication fails first. Inspired by our recent experimental work on ED, we formulated a novel computational model to explore initial events during ED. Our model reproduces time courses for several ions from different experimental data. In some cases, the system returns to baseline upon restoring energy supply. In others, we observe that neurons and astrocytes cannot recover accompanied by cell swelling. There is a threshold depending on the depth and duration of ATP depletion differentiating these cases. Also, smaller extracellular spaces hamper recovery more. This result may explain clinical observations of increased vulnerability to stroke as the size of the extracellular space shrinks with ageing.