Abstract
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 brain's susceptibility to ischemic damage. Our work provides new insights into the brain's ability to recover from energy deprivation, with translational relevance for diagnosis and treatment of ischemic strokes.
Highlights
Information transfer at synapses [1] critically depends on the cellular availability of adenosine triphosphate (ATP), the main energy-carrying molecule in the body
As a result, during ATP depletion, transport of glutamate into presynaptic vesicles is initially diminished, see neuronal excitatory amino acid transporters (EAATs) current in S2 Fig. Further, ion gradients do not return to physiological values, and permanent cell swelling is observed
We present a detailed biophysical model of energy-dependent ion fluxes in different compartments and of changes in cellular membrane potentials of the tripartite synapse to further our understanding of their dynamics in low energy conditions
Summary
Information transfer at synapses [1] critically depends on the cellular availability of adenosine triphosphate (ATP), the main energy-carrying molecule in the body. Depending on the depth and duration of energy deprivation (ED), this is accompanied by a loss of membrane potentials, cell swelling, and, cell death [2, 5,6,7]. Several of these processes are well understood at a phenomenological level. All active transport fluxes have disappeared at this equilibrium, and the membrane potential equals the individual ions’ Nernst potentials This cascade of events is accompanied by failure of cellular glutamate uptake through excitatory amino acid transporters (EAATs), which are mainly expressed by astrocytes [14, 15]. The resulting toxic accumulation of glutamate in the extracellular space (ECS), coupled with intracellular Ca2+ accumulation, triggers neuronal cell death via multiple pathways [16]
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