Episodic neurological disorders are characterized by attacks of debilitating symptoms interspersed with periods of relatively normal function. Although the symptoms can be diverse, including migraine headache, epilepsy, paralysis, ataxia, and dyskinesia, there are marked similarities in both the genetic etiology and the factors capable of triggering attacks in episodic disorders. Many episodic disorders are associated with ion channel mutations. Further, regardless of the class of ion channelopathy or the expressed symptoms, the precipitants of attacks are most commonly psychological, physical or chemical stressors, suggesting the existence of a common mechanism for the initiation of the attacks. There is little understanding of the mechanisms by which these triggers precipitate neurological dysfunction in individuals who are otherwise normal between attacks. Our approach to this problem is to use a rare monogenic disorder as a model system. because understanding pathogenesis in a monogenic episodic disorder will likely provide insight into genetically complex episodic disorders such as migraine headache and idiopathic epilepsy. We have identified episodic ataxia type 2 (EA2), as a leading candidate for modeling this class of disorders in mice. EA2 is caused by mutations in the CACNA1A gene, which encodes the pore-forming a12.1 subunit of Cav2.1 (P/Q-type) voltage-gated calcium channels. This disorder is particularly amenable for modeling because there is already a wealth of basic information on which to build, including an enormous body of work describing normal and mutant Cav2.1 channel properties in vitro. Individuals with episodic ataxia type 2 experience paroxysmal attacks of migraine, ataxia, and other neurological signs that are triggered by emotional stress, exercise, caffeine or ethanol. Although the mutations in CACNA1A were first identified in 1996, the pathogenic mechanisms are still unknown. Functional expression studies of EA2 mutations in heterologous systems demonstrate reduced Cav2.1 currents, as expected. However, there is evidence for both haploinsufficiency and dominant negative effects of the mutant channel, demonstrating that even this most basic of questions requires expression of the mutants in a native in vivo system. Work in both cultured neurons and mouse mutants also demonstrates that an appreciation of the biophysical properties of the mutant channel in vitro is not likely to provide a comprehensive understanding of the phenotype because compensatory processes in neurons in vivo may also contribute. These results demonstrate the need for a behaviorally intact animal model to fully appreciate disease processes. Therefore, we will develop and characterize a knockin mouse bearing an EA2 mutation.
The specific aims of this proposal are 1) To develop and characterize a knockin mouse model of EA2. 2) To behaviorally characterize the EA2 knockin mice. The development of a mouse model will place us in an excellent position to examine pathophysiology and provide insight into human disease. Episodic neurological disorders are characterized by attacks of debilitating symptoms, including migraine headache, epilepsy, paralysis, ataxia, and dyskinesia, interspersed with periods of relatively normal function. There is little understanding of the pathophysiological mechanisms that triggers neurological dysfunction. Therefore, we will develop and characterize a knockin mouse bearing a human mutation for episodic ataxia, a rare monogenic disorder that may provide insight into genetically complex episodic disorders such as migraine headache and idiopathic epilepsy. ? ? ? ?
| Rose, Samuel J; Kriener, Lisa H; Heinzer, Ann K et al. (2014) The first knockin mouse model of episodic ataxia type 2. Exp Neurol 261:553-62 |
