Elevated Expression of the G-Protein-Activated Inwardly Rectifying Potassium Channel 2 (GIRK2) in Cerebellar Unipolar Brush Cells of a Down Syndrome Mouse Model

SUMMARY

1. Down syndrome (DS) arises from the presence of three copies of chromosome (Chr.) 21. Fine motor learning deficits found in DS from childhood to adulthood result from expression of extra genes on Chr. 21, however, it remains unclear which if any of these genes are the specific causes of the cognitive and motor dysfunction. DS cerebellum displays morphological abnormalities that likely contribute to the DS motor phenotype.

2. The G-protein-activated inwardly rectifying potassium channel subunit 2 (GIRK2) is expressed in cerebellum and can shunt dendritic conductance and attenuate postsynaptic potentials. We have used an interbreeding approach to cross a genetic mouse model of DS (Ts65Dn) with Girk2 knockout mice and examined its relative expression level by quantitative real-time RT-PCR, Western blotting and immunohistochemistry.

3. We report here for the first time that GIRK2 is expressed in unipolar brush cells, which are excitatory interneurons of the vestibulocerebellum and dorsal cochlear nucleus. Analysis of disomic-Ts65Dn/Girk2(+/+/−) and heterozygous-Diploid/Girk2(+/−) mice shows that GIRK2 expression in Ts65Dn lobule X follows gene dosage. The lobule X of Ts65Dn mice contain greater numbers of unipolar brush cells co-expressing GIRK2 and calretinin than the control mouse groups.

4. These results demonstrate that gene triplication can impact specific cell types in the cerebellum. We hypothesize that GIRK2 overexpression will adversely affect cerebellar circuitry in Ts65Dn vestibulocerebellum and dorsal cochlear nucleus due to GIRK2 shunting properties and its effects on resting membrane potential.

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ACKNOWLEDGMENTS

The authors wish to thank Mr. Tyler Best and Mrs. Angelina KlineBurgess for assistance with the care and genotyping of the Ts65Dn mice and Ms. Madelaine Cho for running Western blots. We also want to thank Mr. Tyler Best for his help and critical comments during the preparation of the manuscript. This work was supported by NIH grant HD38417, J. Lejeune Foundation and USUHS (ZG) and in part by the Intramural Research Program of NIMH, NIH (DJ), and the Dana Foundation (TH).

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Correspondence to David M. Jacobowitz.

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While Dr. Julius Axelrod’s impact on the development of Neuroscience was significant, one of his major contributions was made indirectly through the people close to him that he influenced. Being a Section Chief and colleague to Julie in the Laboratory of Clinical Science at the National Institute of Mental Health was one of the great honors of my life. It was always a joy observing humility, friendliness and concern of all problems big or small. At laboratory seminars it was a pleasure to watch Julie’s ideas and intuitions that often generated a tremendous amount of good science. He taught all of us how to be curious, incisive and imaginative, and above all to “keep it simple.” His delight in science was contagious. DMJ

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Harashima, C., Jacobowitz, D.M., Stoffel, M. et al. Elevated Expression of the G-Protein-Activated Inwardly Rectifying Potassium Channel 2 (GIRK2) in Cerebellar Unipolar Brush Cells of a Down Syndrome Mouse Model. Cell Mol Neurobiol 26, 717 (2006). https://doi.org/10.1007/s10571-006-9066-4

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KEY WORDS:

  • unipolar brush cells
  • trisomy
  • cerebellum
  • Ts65Dn
  • dorsal cochlear nucleus
  • vestibulocerebellum
  • Girk2 knockout mouse
  • GIRK
  • Down syndrome
  • potassium channel
  • G-protein activated inwardly rectifying potassium channel