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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Christophe Bernard, Aix-Marseille Université, France
- Second opponent: Professor Hajime Hirase, University of Copenhagen,
- Third member and chair of the evaluation committee: Associate Professor Hua Hu, University of Oslo
Chair of the Defence
Associate Professor Torkel Hafting, University of Oslo
Principal Supervisor
Rune Enger, University of Oslo
Summary
Migraine aura is a collection of perceptual symptoms affecting many migraineurs caused by a phenomenon called cortical spreading depression (CSD). Similar processes can occur in ischemic stroke, subarachnoid hemorrhage and traumatic brain injury called spreading depolarizations.
CSD is a self-propagating, slowly moving wave of depolarization of cells which transiently disarranges the tightly regulated homeostasis in the central nervous system. These disturbances include massive extracellular increase in potassium, overflow of neurotransmitters (e.g., glutamate), cellular swelling and hemodynamic fluctuations. Astrocytes belong to a group of cells in the central nervous system called glial cells and maintain homeostasis of nearly all extracellular compounds, including potassium and glutamate. They also possess specialized processes called astrocytic endfeet which envelop the entire cerebral vasculature.
Albeit glutamate is involved in CSD elicitation and propagation the pathophysiology is not fully understood. Moreover, while CSD-related astrocytic swelling has been reported it remained highly controversial. CSD also caused transitory collapse of perivascular brain waste clearance which potentially could be due to astrocytic endfoot swelling.
This thesis studied the role of astrocytes in regulating glutamate and astrocytes’ own cellular volume during CSD using genetically encoded fluorescent sensors and two-photon microscopy in awake and anesthetized transgenic mice.
We demonstrated that CSD induced astrocytic swelling, including in the astrocytic endfeet. The endfoot swelling magnitude was unaffected by the deletion of the water channel aquaporin-4 (AQP4) and was too short to block brain waste clearance. Astrocyte swelling activates the volume-regulated anion channel sub-unit Swell1 and releases glutamate effecting CSD elicitation and propagation. Moreover, we found that the potassium channel Kir4.1 is pivotal for glutamate uptake and alters the threshold to elicit CSD.
Additional information
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