Familial hemiplegic migraine

Area of Science:

• Neurogenetics
• Molecular Neuroscience
• Migraine Pathophysiology

Background:

• Familial hemiplegic migraine (FHM) is a rare, autosomal dominant subtype of migraine with aura.
• Genetic mutations in CACNA1A (FHM1), ATP1A2 (FHM2), and SCNA1A (FHM3) are implicated in FHM.
• Understanding the functional consequences of these mutations is crucial for elucidating migraine mechanisms.

Purpose of the Study:

• To review functional studies of FHM mutations in knockin mice and heterologous expression systems.
• To investigate the impact of FHM-associated gene mutations on neuronal function and cortical spreading depression (CSD).
• To explore the role of CSD and cortical hyperexcitability in migraine pathogenesis and identify potential therapeutic targets.

Main Methods:

• Analysis of functional studies involving two FHM1 knockin mouse models.
• Examination of FHM mutants (12 FHM1, 8 FHM2, 1 FHM3) in heterologous expression systems.
• Correlation of observed molecular/cellular changes with in vivo induction and propagation of cortical spreading depression (CSD).

Main Results:

• FHM1 mutations cause gain-of-function in Ca(V)2.1 channels, increasing neurotransmitter release and facilitating CSD.
• FHM2 mutations result in loss-of-function of the Na+, K+-ATPase alpha2 subunit.
• The FHM3 mutation accelerates the recovery from fast inactivation of Na(V)1.1/1.5 channels, potentially leading to excessive extracellular K+.

Conclusions:

• FHM mutations converge on increasing brain susceptibility to CSD through various mechanisms: excessive glutamate release (FHM1), impaired ion/glutamate clearance (FHM2), or altered K+ homeostasis (FHM3).
• CSD plays a critical role in migraine pathogenesis.
• Cortical hyperexcitability underlies vulnerability to CSD and migraine attacks, suggesting CSD and hyperexcitability as targets for preventive migraine therapies.