The role of the glutamate-glutamine cycle in synaptic transmission during ischemia and recovery

Cerebral ischemia impairs neuronal and glial function, ranging from synaptic failure to irreversible damage. The effects of ischemia on excitatory synaptic transmission remain incompletely understood. Here, we present a detailed biophysical model including the first full implementation of the glutamate-glutamine cycle (GG-cycle), which is essential for proper functioning of glutamatergic synapses. We simulate a presynaptic neuron and an astrocyte in a finite extracellular space (ECS), surrounded by an oxygen bath, as a proxy for energy supply. The model includes ionic currents with corresponding channels and transporters such as the sodium-potassium AT-Pase. To model synaptic transmission, we combine calcium-dependent glutamate release, its uptake by the sodium-dependent excitatory amino acid transporters (EAATs), and the GG-cycle, including glutamine synthesis. We simulate ischemia by blocking energy supply completely. The neuron enters a depolarization block, ion concentrations reach pathological values, and glutamate accumulates in the ECS while glutamate release is disrupted. Surprisingly, we found that synaptic transmission failure was not primarily caused by excessive glutamate release nor by failure of glutamine synthetase. Instead, it mainly resulted from EAAT dysfunction, driven by the collapse of the sodium gradient. Enhancing glutamate clearance alone was insufficient for recovery of synaptic transmission. However, inhibition of the voltage-gated Na+ channels restored ion gradients, recovered glutamate uptake, and re-enabled glutamate release. Taken together, our study highlights the critical role of ion homeostasis, in particular the sodium gradient, in maintaining synaptic function during metabolic stress. Moreover, the model provides a better understanding of synaptic transmission failure and potential recovery strategies during ischemia.