Altered responses to potassium in cerebellar neurons from weaver heterozygote mice

A. P. Fox, Stephen Dlouhy, Bernardino Ghetti, Joyce Hurley, P. G P Nucifora, D. J. Nelson, L. Won, A. Heller

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The pleiotropic weaver disease is caused by the mutation of a single amino acid in the G-protein-linked inwardly rectifying K+ channel, GIRK2. In homozygous (wv/wv) animals, the disease is characterized by loss of cerebellar and dopaminergic mesencephalic neurons as well as testicular cells, which produce ataxia, fine tremors, and sterility, respectively. Heterozygous (wv/+) animals show no obvious motor impairments, although some loss of both cerebellar and dopaminergic neurons is observed and wv/+ males become sterile at 3.5 months of age. Abnormal influxes of Na+ and Ca2+ have been linked to cerebellar cell death in wv/wv animals, but it's not clear whether similar changes are observed in wv/+ animals. To discover whether changes in K+-channel function or intracellular Ca2+ concentrations ([Ca2+](i)) play a role in the augmented cell loss observed in wv/+ animals when compared with +/+ animals, we studied cultured cerebellar granule cells prepared from either wv/+ or +/+ animals. Resting [Ca2+](i) was elevated in wv/+ relative to +/+ animals. Further, depolarizations of cells with elevated K+ solutions elicited much smaller changes in [Ca2+](i) in wv/+ animals than in +/+ animals, presumably due to altered GIRK2 channel function. Both wv/+ and +/+ cells showed similar changes in [Ca2+](i) when cells were depolarized by glutamate (1 mM), suggesting that both glutamate receptors and Ca2+ channels were unchanged in wv/+ animals. In summary, our results suggest that wv/+ cerebellar granule cells exhibit elevated resting [Ca2+](i) levels and altered K+-channel function, which may contribute to the developmental abnormalities and increased cell death observed.

Original languageEnglish
Pages (from-to)298-306
Number of pages9
JournalExperimental Brain Research
Volume123
Issue number3
DOIs
StatePublished - 1998

Fingerprint

Neurologic Mutant Mice
Heterozygote
Potassium
Neurons
Dopaminergic Neurons
Cell Death
Inwardly Rectifying Potassium Channel
Animal Diseases
Glutamate Receptors
Tremor
Ataxia
GTP-Binding Proteins
Infertility
Glutamic Acid

Keywords

  • Calcium
  • Cerebellar granule cells
  • GIRK2
  • Heterozygote
  • Weaver mice

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Altered responses to potassium in cerebellar neurons from weaver heterozygote mice. / Fox, A. P.; Dlouhy, Stephen; Ghetti, Bernardino; Hurley, Joyce; Nucifora, P. G P; Nelson, D. J.; Won, L.; Heller, A.

In: Experimental Brain Research, Vol. 123, No. 3, 1998, p. 298-306.

Research output: Contribution to journalArticle

Fox, A. P. ; Dlouhy, Stephen ; Ghetti, Bernardino ; Hurley, Joyce ; Nucifora, P. G P ; Nelson, D. J. ; Won, L. ; Heller, A. / Altered responses to potassium in cerebellar neurons from weaver heterozygote mice. In: Experimental Brain Research. 1998 ; Vol. 123, No. 3. pp. 298-306.
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abstract = "The pleiotropic weaver disease is caused by the mutation of a single amino acid in the G-protein-linked inwardly rectifying K+ channel, GIRK2. In homozygous (wv/wv) animals, the disease is characterized by loss of cerebellar and dopaminergic mesencephalic neurons as well as testicular cells, which produce ataxia, fine tremors, and sterility, respectively. Heterozygous (wv/+) animals show no obvious motor impairments, although some loss of both cerebellar and dopaminergic neurons is observed and wv/+ males become sterile at 3.5 months of age. Abnormal influxes of Na+ and Ca2+ have been linked to cerebellar cell death in wv/wv animals, but it's not clear whether similar changes are observed in wv/+ animals. To discover whether changes in K+-channel function or intracellular Ca2+ concentrations ([Ca2+](i)) play a role in the augmented cell loss observed in wv/+ animals when compared with +/+ animals, we studied cultured cerebellar granule cells prepared from either wv/+ or +/+ animals. Resting [Ca2+](i) was elevated in wv/+ relative to +/+ animals. Further, depolarizations of cells with elevated K+ solutions elicited much smaller changes in [Ca2+](i) in wv/+ animals than in +/+ animals, presumably due to altered GIRK2 channel function. Both wv/+ and +/+ cells showed similar changes in [Ca2+](i) when cells were depolarized by glutamate (1 mM), suggesting that both glutamate receptors and Ca2+ channels were unchanged in wv/+ animals. In summary, our results suggest that wv/+ cerebellar granule cells exhibit elevated resting [Ca2+](i) levels and altered K+-channel function, which may contribute to the developmental abnormalities and increased cell death observed.",
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AU - Dlouhy, Stephen

AU - Ghetti, Bernardino

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AU - Nelson, D. J.

AU - Won, L.

AU - Heller, A.

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