Episodic Ataxia / Myokymia Syndrome Type 1 (EA1) is an inherited autosomal dominant human neurological disorder. The principal symptoms of EA1 are myokymia and episodic attacks of generalized ataxia that are diminished by carbonic anhydrase inhibitors such as acetazolamide. EA1 is due to missense point mutations in KCNA1, the gene encoding the voltage-gated delayed rectifier potassium channel, Kv1.1; most mutations alter the biophysical properties of Kv1.1 channels. In the cerebellum, Kv1.1 is localized to axonal branch points and the pinceau synaptic structure of GABAergic interneurons that innervate the Purkinje cells. To understand the cellular consequences of EA1 mutations in Kv1.1 that result in ataxia, and the mechanism by which acetazolamide reduces the ataxia, ES cell-mediated homologous recombination was used to produce a transgenic mouse model of EA1 harboring the EA1 mutation V408A. In the EA1 mice, cerebellar Purkinje neurons show increased frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs). Two overall aspects will be investigated. First, the mouse model will be evaluated for EA1 using a battery of behavioral tests for motor coordination and the efficacy of acetazolamide. Second, the cellular basis of ataxia in EA1 mice will be examined using paired recordings from presynaptic basket cells and postsynaptic Purkinje cells in cerebellar slices, coupled with Ca2+ imaging. Four specific hypotheses will be tested: 1) Transgenic mice harboring the V408A allele provide an animal mode/for human EA1. 2) The increased frequency of spontaneous Purkinje cell IPSCs in EA1 mice results from reduced failure of action potential propagation at branch points along the basket cell axon. 3) The increased amplitude of Purkinje cell IPSCs in EA1 mice results from reduced failure of action potential propagation within the synaptic terminals of the basket cell, the pinceaus. 4) The higher GABAergic activity in EA1 basket cells predisposes the Purkinje cells to a transformation from a hyperpolarizing to depolarizing postsynaptic potential. Acetazolamide, by minimizing repair of the HCO3 gradient, reduces the depolarizing GABAA signal transformation, thus maintaining an inhibitory postsynaptic response to GABAA. These experiments will establish a link between altered electrophysiology and behavior in EA1 and demonstrate a precise connection between altered Kvl.1 channel biophysical function and the consequence of the altered channel function in neurons in rive. The use of transgenic technology to develop mouse models of disease will permit an understanding of EA1 and the possibility of new pharmacological treatments for this disease.
| Luján, Rafael; Maylie, James; Adelman, John P (2009) New sites of action for GIRK and SK channels. Nat Rev Neurosci 10:475-80 |
