A novel signaling pathway identified in auditory migraines

Rapid influx of cerebrospinal fluid (CSF) and protein solutes released during widespread cortical depression (ECD) in the brain activates neurons to trigger auditory migraines, according to a new study in mice. The findings identify a novel nonsynaptic signaling mechanism between the brain and the peripheral sensory system important for migraine. They also suggest potential drug targets for treating this painful disorder.

Migraine with aura, or auditory migraine, is a distinct headache disorder that may include sensory disturbances, such as hearing or vision-related symptoms that precede the onset of head pain. During the aura phase, CSD waves are thought to be spontaneously triggered in the cerebral cortex or cerebellum, which, in turn, lead to activation of pain receptors (nociceptors) in the peripheral nervous system (PNS). Previous research has suggested that CSD events release small molecules through the CSF that activate sensory nerve endings in the external tissues of the CNS (central nervous system), “outside” the blood-brain barrier. These nerve endings are not exposed to the CSF. How pathological CSD events in the cortex trigger activation of peripheral nociceptors outside the brain remains poorly understood. Using a combination of proteomic, histological, imaging, and functional approaches in a mouse model of classical migraine, Martin Rasmussen and colleagues identified a signaling pathway between the CNS and the PNS at the level of the trigeminal ganglion. Unlike more distal parts of the CNS, the proximal area of ​​the trigeminal ganglion does not have a tight nerve barrier, allowing CSF and signaling molecules released during CSD events to enter and interact with trigeminal cells.

Rasmussen et al. The authors found that CSD altered 11% of the CSF proteome, with upregulation of proteins that directly activate trigeminal ganglion receptors, including calcitonin gene-related peptide (CGRP). “While this work provides some of the strongest evidence to date on the role of the glymphatic system in migraine, much remains to be learned about the fundamental role that fluid and solute transport plays in neurobiological processes, suggesting that the journey toward understanding the role of glymphatic function and dysfunction in a broad range of neurological and psychiatric disorders is only just beginning,” write Andrew Russo and Jeffery Iliff in a companion Perspective article.