A mouse model of episodic ataxia type-1.
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.
Herson
Paco S
PS
Vollum Institute, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
Virk
Michael
M
Rustay
Nathan R
NR
Bond
Chris T
CT
Crabbe
John C
JC
Adelman
John P
JP
Maylie
James
J
D000086:Acetazolamide / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002256:Carbonic Anhydrases / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005804:Genes, Lethal / Q000235:genetics; D051662:Kv1.1 Potassium Channel; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
C496947:Kcna1 protein, mouse; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051662:Kv1.1 Potassium Channel; D005680:gamma-Aminobutyric Acid; D002256:Carbonic Anhydrases; D000086:Acetazolamide