A genetic dysfunction in specific brain cells strongly influences head pain occurrence, neuroscientists of the University of Zurich report[1]. This familial hemiplegic migraine type 2 (FHM2) causes a malfunction of astrocytes in the cingulate cortex, a brain region that is involved in the feeling of pain.

Migraine is one of the most disabling neurological disorders, affecting one in seven people and causing a tremendous social and economic burden. Several findings suggest that migraine is a disease affecting a large part of the central nervous system and characterized by a global dysfunction in sensory information processing and integration, which also occurs between migraine episodes (interictal period).

For example, patients with migraine exhibit increased cortical responses to sensory stimuli during the interictal period. At present, the cellular mechanisms responsible for these alterations are largely unknown.

Relatively Overlooked

Astrocytes, specific star-shaped brain cells, are essential contributors to neuronal function and have a strong impact on brain circuits and behavior.

“Despite their abundance, astrocytes have been relatively overlooked by neuroscientists,"

says Mirko Santello, last author of the study. Yet these cells are extremely important to clear transmitters released by neurons.

In their study the researchers were able to show that in familial migraine the astrocytes cannot remove excessive transmitters released by neurons.

“The impairment in astrocytic glutamate uptake in the cingulate cortex strongly enhances cortical dendritic excitability and thus enhances firing of the neurons,"

Santello says.

Genetic Manipulations

Furthermore, the study reported that the malfunction of the cingulate cortex also influences migraine occurrence. In a mouse model the researchers showed that the mice displayed increased sensitivity to head pain triggers.

“By manipulating astrocytes in the cingulate cortex, we were able to reverse their dysfunction. This prevented an increase in head pain in mice carrying the genetic defect,"

says Jennifer Romanos, first author of the study.

[caption id=“attachment_103263” align=“aligncenter” width=“700”]NMDA spike generation Facilitation of NMDA spike generation in L5 pyramidal neurons in the Cg of FHM2 mice.
Credit: J. Romanos, et al CC-BY[/caption]

Migraine is a complicated disorder that affects part of the nervous system.

“Our results provide a clear example of how astrocyte dysfunction produced by a genetic defect affects neuronal activity and sensitivity to head pain triggers,"

explains Mirko Santello. The findings help to better understand migraine pathophysiology and suggest that the cingulate cortex may represent a critical hub in the disease.

The demonstration of the link between dysfunction of astrocytes in the cingulate cortex and familial migraine could help in devising new migraine treatment strategies. The research was supported by the Swiss National Science Foundation, Novartis Foundation for medical-biological Research, and the Hartmann-Müller Stiftung.

[1] Jennifer Romanos, Dietmar Benke, Daniela Pietrobon, Hanns Ulrich Zeilhofer, and Mirko Santello. Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine. Science Advances 05 Jun 2020: Vol. 6, no. 23, eaaz1584 DOI: 10.1126/sciadv.aaz1584

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