Migraine is one of the most common neurovascular disorders with noticeable genetic predisposition. Understanding the mechanisms of migraine will lead to more specific treatments. Familial Hemiplegic Migraine (FHM), a rare hereditary form of migraine with aura and hemiparesis, serves as a good model for exploring migraine pathophysiology. The gene for FHM type 1 (FHM-1) encodes the pore-forming 1A subunit of P/Q- type voltage-gated Ca2+ channels - a key player in supporting voltage-dependent Ca2+ entry that is critical for neurotransmitter release at presynaptic terminals and postsynaptic Ca2+ signaling in soma and dendrites. The discovery of multiple 1A mutations in FHM-1 patients provides a platform for elucidating the mechanism underlying FHM-1 as well as migraine in general. We have initiated experiments to explore the effects of T666M, the most frequently occurring FHM-1 mutation, on voltage-dependent Ca2+ influx in neurons from the trigeminal nociceptive pathway responsible for headache pain generation. Our preliminary studies indicate that T666M results in a decrease of Ca2+ influx through P/Q- type channels in cultured neurons from trigeminal ganglion as well as cervical dorsal horn. Interestingly, a consequent increase of low-voltage gated T-type current is only observed in the small peptidergic trigeminal ganglion neurons. The research objective of this proposal is to further investigate the functional consequences of the T666M mutation in trigeminal ganglion and dorsal horn neurons. We hypothesize that loss-of-function FHM-1 mutations as represented by T666M may increase the gain of trigeminal nociceptive circuitry via two possible scenarios: 1) increasing the excitability of trigeminal primary afferent neurons and 2) preferentially weakening the inhibitory synaptic transmission at cervical/medullary dorsal horn. In the first aim, we will examine the effect of T666M mutant channels on neuronal excitability using current clamp recordings.
The second aim of the proposal addresses how T666M mutant channels affect synaptic transmission from nociceptive neurons. In addition, we will use tottering, mice with a loss-of-function 1A mutation, as experimental model to test the effect of defect P/Q-type channels on the excitability and neurotransmission of trigeminal nociceptive neurons. Together, these experiments will not only increase our understanding of the contribution of voltage-gated Ca2+ channels to FHM-1 and general migraine pathophysiology;but also shed light on the mechanisms underlying other forms of headache. Importantly, these studies will lay ground work for future investigations of the functional consequences of FHM-1 mutations in the context of trigeminal nociceptive circuit as well as from a systems neurobiology perspective.

Public Health Relevance

Migraine is one of the most common neurovascular disorders and an enormous burden to the healthcare system. Understanding the disease mechanisms will greatly facilitate drug development for both preventive and palliative therapies of migraine. Multiple mutations in human P/Q-type voltage-gated Ca2+ channels have been associated with familial hemiplegic migraine type 1 (FHM-1) - a hereditary form of migraine. We propose to study the functional consequences of T666M, the most frequently occurred mutation, as a gateway towards understanding the mechanisms underlying migraine headache.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Porter, Linda L
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Washington University
Schools of Medicine
Saint Louis
United States
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