[Abstract Title]. - Society for Neuroscience

Authors: *C. F. BARRETT 1 , L. A. M. BROOS 2 , R. R. FRANTS 2 , M. D. FERRARI 2 , A. M. J.
M. VAN DEN MAAGDENBERG 2 ;
1 Neurol and Human Genet., 2 Leiden Univ. Med. Ctr., Leiden, Netherlands
Abstract: Migraine is one of the most common neurological disorders, affecting up to 12% of
the general population on a chronic basis. In one third of migraine patients, the headache is
preceded by an aura. Spreading depression is a self-propagating wave of transient depolarization
of neuronal and glial cells. Spreading depression in the cerebral cortex (CSD) is believed to
underlie the aura phase of the attack and may also trigger the headache phase itself, possibly by
activating neurons within the trigeminovascular nucleus. However, whether CSD is either
necessary and/or sufficient to induce a migraine attack is not known. In an attempt to understand
what makes the migraine brain more susceptible to the effects of spreading depression, we
examined which brain regions are activated by CSD events, using c-Fos expression as a marker
of neuronal activation. We compared activation patterns between wild-type (i.e., non-migraine)
mice and two lines of mice carrying missense mutations in the Cacna1a gene linked to familial
hemiplegic migraine (FHM), a monogenic subtype of migraine with aura. The R192Q mutation
models “pure” FHM in patients, while the S218L mutation, although quite close to position 192
in primary structure, causes a much more severe clinical outcome, including not only FHM but
also ataxia, seizures, and coma and cerebral edema following mild head trauma. Consistent with
these overlapping yet different clinical phenotypes, we found that CSD activates both
overlapping and distinct brain regions in the FHM mutant mice. Specifically, in the S219L brain,
CSD events and seizures both drive strong activation of neurons in the cerebral cortex and
hippocampus. However, CSD events but not seizures activate Purkinje neurons in the
cerebellum. Moreover, in wild-type and R192Q mice, CSD events activate neurons in the
cerebral cortex but not the hippocampus or cerebellum. These findings provide clues to the
pathophysiology of these two seemingly distinct episodic events, and help explain the disparate
clinical findings in R192Q and S218L patients.
Disclosures: C.F. Barrett, None; L.A.M. Broos, None; R.R. Frants, None; M.D. Ferrari,
None; A.M.J.M. van den Maagdenberg, None.
Poster
235. Ion Channels in Disease I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 235.2/C48
Topic: B.04.d. Ion channels and disease
Support: European Integrated Project Epicure