Inadequate brain glycogen or sleep increases spreading depression susceptibility

Area of Science:

• Neuroscience
• Astrocyte Biology
• Migraine Pathophysiology

Background:

• Astrocyte glycogen supports synaptic function by maintaining low extracellular glutamate and K+.
• Sleep deprivation (SD), a migraine trigger, reduces astrocyte glycogen breakdown.
• Impaired glycogen utilization may lead to elevated extracellular K+, activating neuronal pannexin-1 channels and inflammatory pathways, potentially initiating migraine headaches.

Purpose of the Study:

• To investigate the hypothesis that reduced glycogen utilization during sleep deprivation (SD) or pharmacological inhibition leads to elevated extracellular K+ and migraine initiation.
• To explore the role of astrocyte glycogen in regulating extracellular K+ and preventing neuronal activation and cortical spreading depression (CSD).

Main Methods:

• Suppressed glycogen breakdown using 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and sleep deprivation (SD).
• Assessed pannexin-1 channel activation (procaspase-1 cleavage, HMGB1 release) and CSD threshold.
• Measured extracellular K+ using a selective fluoroprobe during whisker stimulation.

Main Results:

• DAB induced pannexin-1 channel opening and inflammation; SD increased pannexin-1 mRNA.
• Both DAB and SD lowered the CSD induction threshold, reversible by glucose or lactate.
• Reduced glycogen-derived substrates (via MCT2 knockdown or phloretin) lowered CSD threshold; DAB/SD elevated extracellular K+.

Conclusions:

• Synaptic metabolic stress from insufficient glycogen impairs energy supply, activating pannexin-1 channels and lowering the CSD threshold.
• Conditions limiting synaptic energy, such as SD, may predispose individuals to migraines.
• Astrocyte glycogen is crucial for maintaining extracellular K+ homeostasis and preventing CSD.