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A mouse model of episodic ataxia type-1

Abstract

Episodic ataxia type-1 (EA1) is a dominant human neurological disorder characterized by stress-induced attacks of ataxia. EA1 is caused by mutations in the voltage-gated potassium channel Kv1.1, and affected individuals are heterozygous. Here we introduced the V408A EA1 mutation into mice using homologous recombination. In contrast to Kv1.1 null mice, homozygous V408A/V408A mice died after embryonic day 3 (E3). V408A/+ mice showed stress-induced loss of motor coordination that was ameliorated by acetazolamide, a carbonic anhydrase inhibitor that minimizes EA1 symptoms in human patients. We made electrophysiological recordings from cerebellar Purkinje cells in both V408A/+ mice and their wild-type littermates. V408A/+ mice showed a greater frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) than did wild type; however, the amplitude or frequency of miniature IPSCs and the basket cell firing frequency did not differ between groups. The stress-induced motor dysfunction in V408A mice is similar to that of family members harboring the EA1 allele, and our findings suggest that these behavioral changes are linked to changes in GABA release.

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Figure 1: The V408A point mutation is homozygous lethal.
Figure 2: Stress induced loss of motor coordination in V408A/+ mice.
Figure 3: Increased frequency and amplitude of sIPSCs recorded in cerebellar Purkinje cells from V408A/+ mice.
Figure 4: V408A/+ mice do not show altered mIPSCs.
Figure 5: V408A/+ mice do not show altered basket cell firing rates.

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Acknowledgements

We thank V. Devignot for help with genotyping the mice. This work was supported by a National Research Service Award (NRSA) grant to N.R.R. and grants from the National Institutes of Health to J.C.C., J.P.A and J.M. and from Veterans Affairs to J.C.C.

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Correspondence to James Maylie.

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Herson, P., Virk, M., Rustay, N. et al. A mouse model of episodic ataxia type-1. Nat Neurosci 6, 378–383 (2003). https://doi.org/10.1038/nn1025

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