Targeting Spreading Depolarizations to safeguard neuronal ATP

• Applicant: Karl Schoknecht, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 578760032

Spreading depolarizations (SD) are propagating waves of neuronal and glial depolarization characterized by the near-complete breakdown of transmembrane ion gradients. They have been observed in patients with acute brain injuries such as subarachnoid hemorrhage, ischemic stroke, and traumatic brain injury, where they are associated with lesion progression. The detrimental effects of SDs have been largely attributed to a mismatch between energy supply and demand, arising i.a. from the increased energy demand required to restore ion gradients. However, the precise effects of SDs on neuronal energy metabolism remain largely unknown. The advent of cell type-specific, genetically encoded, optical nanosensors for metabolites now allows investigating these processes experimentally at single-cell resolution. Using such tools, we recently demonstrated that SDs cause a transient decrease in neuronal levels of adenosine triphosphate (ATP), an essential energy-rich compound, despite continuous supply of oxygen and glucose, which confirms a mismatch between ATP synthesis and consumption. Notably, under oxygen and glucose deprivation – an in vitro stroke model – neuronal ATP did not decrease gradually but instead dropped sharply in the course of SDs. SDs thus represent a promising therapeutic target to protect neuronal ATP. In this project, I will investigate whether neuroprotective strategies to prevent SDs can protect neurons from potentially irreversible ATP depletion. Furthermore, I aim to identify molecular mechanisms that directly influence neuronal ATP synthesis and will test them therapeutically. Based on our recent study, I hypothesize that SDs temporarily inhibit ATP synthesis despite increased ATP demand, which would further exacerbate energy deficiency and promote neuronal damage. To test this hypothesis, I will use optical nanosensors to monitor not only ATP but also principal pathways of ATP synthesis. In addition to the acute effect of SDs on neuronal ATP, I will investigate whether SDs advance the tipping point at which energy metabolism irreversibly fails under oxygen and glucose deprivation. Confirming such an effect would further highlight SDs as a pivotal therapeutic target. In summary, this project will investigate the impact of SDs on neuronal energy metabolism – using optical nanosensors at single-cell resolution – to subsequently develop and test therapeutic approaches in a stroke model.

• DFG Programme: Research Grants