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Striatal Potassium Channel Dysfunction in Huntington's Disease Transgenic Mice

¹Mental Retardation Research Center and ²Department of Physiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, California; ³Department of Medicine, Division of Endocrinology, Massachusetts Medical Center, Worcester, Massachusetts; ⁴Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts; and ⁵Department of Neuroscience, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois

Submitted 4 August 2004; accepted in final form 23 December 2004

Huntington's disease (HD) is a neurodegenerative disorder that mainly affects the projection neurons of the striatum and cerebral cortex. Genetic mouse models of HD have shown that neurons susceptible to the mutation exhibit morphological and electrophysiological dysfunctions before and during development of the behavioral phenotype. We used HD transgenic mouse models to examine inwardly and outwardly rectifying K⁺ conductances, as well as expression of some related K⁺ channel subunits. Experiments were conducted in slices and dissociated cells from two mouse models, the R6/2 and TgCAG100, at the beginning and after full development of overt behavioral phenotypes. Striatal medium-sized spiny neurons (MSNs) from symptomatic transgenic mice had increased input resistances, depolarized resting membrane potentials, and reductions in both inwardly and outwardly rectifying K⁺ currents. These changes were more dramatic in the R6/2 model than in the TgCAG100. Parallel immunofluorescence studies detected decreases in the expression of K⁺ channel subunit proteins, Kir2.1, Kir2.3, and Kv2.1 in MSNs, which contribute to the formation of the channel ionophores for these currents. Attenuation in K⁺ conductances and channel subunit expression contribute to altered electrophysiological properties of MSNs and may partially account for selective cellular vulnerability in the striatum.

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