A Cacna1a Knockin Migraine Mouse Model with Increased Susceptibility to Cortical Spreading Depression

Abstract

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.

Familial Hemiplegic Migraine

“…31,35 Accordingly, at low voltages close to the threshold of activation of mutant channels, the gainof-function of the Ca V 2.1 current was larger in S218L KI mice than in R192Q KI mice. 39,41 The changes in whole-cell Ca V 2.1 current density in neurons from knockin mice were very similar to the changes in single channel Ca 2ϩ influx of mutant recombinant human Ca V 2.1 channels, indicating that FHM1 mutations produce a similar gain-of-function of Ca 2ϩ influx through mouse and human Ca 2ϩ channels. The analysis of mutant channels in neurons of knockin mice revealed that FHM1 mutations produce gain of function of Ca V 2.1 channels at both the single channel and wholecell level.…”

“…[39][40][41] The studies in heterologous expression systems showed that the FHM1 mutations alter many biophysical properties of human Ca V 2.1 channels, in a complex way. In some cases (e.g., in the case of the channel inactivation properties) the effects were different depending on the mutation.…”

“…Consistent (and in the majority of cases significant) shifts to lower voltages of current activation of human FHM1 mutants were also revealed by measurements of whole-cell currents in heterologous expression systems, transfected neurons and neurons of FHM1 knockin mice. 30,31,[34][35][36][39][40][41] The Ca V 2.1 current density in cerebellar granule cells and cortical pyramidal neurons of R192Q and S218L knockin mice was larger than in wild-type neurons for a wide range of mild depolarizations. Similar current densities were measured with strong depolarizations (eliciting maximal channel open probability) indicating a similar number of functional Ca V 2.1 channels in the membrane of knockin and wild-type neurons.…”

“…Similar current densities were measured with strong depolarizations (eliciting maximal channel open probability) indicating a similar number of functional Ca V 2.1 channels in the membrane of knockin and wild-type neurons. [39][40][41] The shift to lower voltages of Ca V 2.1 channel activation and the gain-of-function of the neuronal Ca V 2.1 current were about twice as large in homozygous compared with heterozygous S218L KI mice, revealing an allele-dosage effect consistent with dominance of the mutation in FHM1 patients. 41 While the R192Q mutation produces a pure FHM phenotype characterized by typical attacks, the S218L mutation produces a severe clinical phenotype, in which typical attacks of FHM triggered by minor head trauma are frequently followed by deep coma or profound stupor (sometimes preceded by a generalized seizure), fever, and long-lasting severe cerebral edema; other common symptoms are ataxia and cerebral and (or) cerebellar atrophy.…”

Role of cortical spreading depression in the pathophysiology of migraine

“…These results indicate that the excitability of the cerebral cortex might be increased by chronic dysfunction of serotonergic innervation in the cerebral cortex, and such a mechanism would explain the facilitation of migraine with a low serotonin disposition. Likewise, increased excitability of the cerebral cortex caused by gene mutation, such as missense mutation of CACNA1A (encoding the α 1 subunit of neuronal Cav2.1(P/Q-type) calcium channels), a representative gene mutation in familial hemiplegic migraine (FHM) families, induces migraine susceptibility by lowering the threshold of cortical SD generation [55] . …”