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

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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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REFERENCES

  • Abbott, L. C., and Jacobowitz, D. M. (1995). Development of calretinin-immunoreactive unipolar brush-like cells and an afferent pathway to the embryonic and early postnatal mouse cerebellum. Anat Embryol (Berl) 191:541–559.

    CAS  Google Scholar 

  • Arai, R., Winsky, L., Arai, M., and Jacobowitz, D. M. (1991). Immunohistochemical localization of calretinin in the rat hindbrain. J. Comp. Neurol. 310:21–44.

    Article  PubMed  CAS  Google Scholar 

  • Aylward, E. H., Burt, D. B., Thorpe, L. U., Lai, F., and Dalton, A. (1997). Diagnosis of dementia in individuals with intellectual disability. J. Intellect. Disabil. Res. 41:152–164.

    PubMed  Google Scholar 

  • Aylward, E. H., Li, Q., Honeycutt, N. A., Warren, A. C., Pulsifer, M. B., Barta, P. E., Chan, M. D., Smith, P. D., Jerram, M., and Pearlson, G. D. (1999). MRI volumes of the hippocampus and amygdala in adults with Down’s syndrome with and without dementia. Am. J. Psychiatry. 156:564–568.

    PubMed  CAS  Google Scholar 

  • Balkany, T. J., Downs, M. P., Jafek, B. W., and Krajicek, M. J. (1979). Hearing loss in Down’s syndrome. A treatable handicap more common than generally recognized. Clin. Pediatr. (Phila) 18:116–118.

    Article  CAS  Google Scholar 

  • Baxter, L. L., Moran, T. H., Richtsmeier, J. T., Troncoso, J., and Reeves, R. H. (2000). Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Hum. Mol. Genet. 9:195–202.

    Article  PubMed  CAS  Google Scholar 

  • Billups, D., Liu, Y. B., Birnstiel, S., and Slater, N. T. (2002). NMDA receptor-mediated currents in rat cerebellar granule and unipolar brush cells. J. Neurophysiol. 87:1948–1959.

    PubMed  CAS  Google Scholar 

  • Braak, E., and Braak, H. (1993). The new monodendritic neuronal type within the adult human cerebellar granule cell layer shows calretinin-immunoreactivity. Neurosci. Lett. 154:199–202.

    Article  PubMed  CAS  Google Scholar 

  • Costa, A. C., Walsh, K., and Davisson, M. T. (1999). Motor dysfunction in a mouse model for Down syndrome. Physiol. Behav. 68:211–220.

    Article  PubMed  CAS  Google Scholar 

  • Dascal, N. (1997). Signalling via the G protein-activated K+ channels. Cell Signal. 9:551–573.

    Article  PubMed  CAS  Google Scholar 

  • Daum, I., and Ackermann, H. (1995). Cerebellar contributions to cognition. Behav. Brain. Res. 67:201–210.

    Article  PubMed  CAS  Google Scholar 

  • Dino, M. R., Nunzi, M. G., Anelli, R., and Mugnaini, E. (2000). Unipolar brush cells of the vestibulocerebellum: afferents and targets. Prog. Brain Res. 124:123–137.

    PubMed  CAS  Google Scholar 

  • Dolan, R. J. (1998). A cognitive affective role for the cerebellum. Brain 121(Pt 4):545–546.

    Google Scholar 

  • Floris, A., Dino, M., Jacobowitz, D. M., and Mugnaini, E. (1994). The unipolar brush cells of the rat cerebellar cortex and cochlear nucleus are calretinin-positive: a study by light and electron microscopic immunocytochemistry. Anat. Embryol. (Berl.) 189:495–520.

    Article  CAS  Google Scholar 

  • Frangou, S., Aylward, E., Warren, A., Sharma, T., Barta, P., and Pearlson, G. (1997). Small planum temporale volume in Down’s syndrome: a volumetric MRI study. Am. J. Psychiatry 154:1424–1429.

    PubMed  CAS  Google Scholar 

  • Frith, U. (1974). Scanning for reversed and rotated targets. Acta Psychol. (Amst.) 38:343–349.

    Article  CAS  Google Scholar 

  • Gitton, Y., Dahmane, N., Baik, S., Altaba, A., Neidhardt, L., Scholze, M., Herrmann, B. G., Kahlem, P., Benkahla, A., Schrinner, S., Yildirimman, R., Herwig, R., Lehrach, H., and Yaspo, M. L. (2002). A gene expression map of human chromosome 21 orthologues in the mouse. Nature 420:586–590.

    Article  PubMed  CAS  Google Scholar 

  • Harashima, C., Jacobowitz, D. M., Jassir, W., Borke, R. C., Best, T., Siarey, R. J., and Galdzicki, Z. (2006). Abnormal expression of the GIRK2 potassium channel in hippocampus, frontal cortex and substantia nigra of Ts65Dn mouse: a model of Down syndrome. J. Comparat. Neurol. 494:815–833.

    Article  CAS  Google Scholar 

  • Harkins, A. B., and Fox, A. P. (2002). Cell death in weaver mouse cerebellum. Cerebellum 1:201–206.

    Article  PubMed  Google Scholar 

  • Hassmann, E., Skotnicka, B., Midro, A. T., and Musiatowicz, M. (1998). Distortion products otoacoustic emissions in diagnosis of hearing loss in Down syndrome. Int. J. Pediatr. Otorhinolaryngol. 45:199–206.

    Article  PubMed  CAS  Google Scholar 

  • Ieshima, A., Kisa, T., Yoshino, K., Takashima, S., and Takeshita, K. (1984). A morphometric CT study of Down’s syndrome showing small posterior fossa and calcification of basal ganglia. Neuroradiology 26:493–498.

    Article  PubMed  CAS  Google Scholar 

  • Isomoto, S., Kondo, C., and Kurachi, Y. (1997). Inwardly rectifying potassium channels: their molecular heterogeneity and function. Jpn. J. Physiol. 47:11–39.

    Article  PubMed  CAS  Google Scholar 

  • Isomoto, S., and Kurachi, Y. (1996). [Molecular and biophysical aspects of potassium channels]. Nippon Rinsho. 54:660–666.

    PubMed  CAS  Google Scholar 

  • Jaarsma, D., Dino, M. R., Ohishi, H., Shigemoto, R., and Mugnaini, E. (1998). Metabotropic glutamate receptors are associated with non-synaptic appendages of unipolar brush cells in rat cerebellar cortex and cochlear nuclear complex. J. Neurocytol. 27:303–327.

    Article  PubMed  CAS  Google Scholar 

  • Kalinichenko, S. G., and Okhotin, V. E. (2005). Unipolar brush cells–a new type of excitatory interneuron in the cerebellar cortex and cochlear nuclei of the brainstem. Neurosci. Behav. Physiol. 35:21–36.

    Article  PubMed  CAS  Google Scholar 

  • Kanold, P. O., and Young, E. D. (2001). Proprioceptive information from the pinna provides somatosensory input to cat dorsal cochlear nucleus. J. Neurosci. 21:7848–7858.

    PubMed  CAS  Google Scholar 

  • Karschin, C., Dissmann, E., Stuhmer, W., and Karschin, A. (1996). IRK(1-3) and GIRK(1-4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain. J. Neurosci. 16:3559–3570.

    PubMed  CAS  Google Scholar 

  • Kinney, G. A., Overstreet, L. S., and Slater, N. T. (1997). Prolonged physiological entrapment of glutamate in the synaptic cleft of cerebellar unipolar brush cells. J. Neurophysiol. 78:1320–1333.

    PubMed  CAS  Google Scholar 

  • Latash, M. L., and Corcos, D. M. (1991). Kinematic and electromyographic characteristics of single-joint movements of individuals with Down syndrome. Am. J. Ment. Retard. 96:189–201.

    PubMed  CAS  Google Scholar 

  • Lesage, F., Duprat, F., Fink, M., Guillemare, E., Coppola, T., Lazdunski, M., and Hugnot, J. P. (1994). Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain. FEBS Lett. 353:37–42.

    Article  PubMed  CAS  Google Scholar 

  • Lesage, F., Guillemare, E., Fink, M., Duprat, F., Heurteaux, C., Fosset, M., Romey, G., Barhanin, J., and Lazdunski, M. (1995). Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J. Biol. Chem. 270:28660–28667.

    Article  PubMed  CAS  Google Scholar 

  • Levine, R. A. (1999). Somatic (craniocervical) tinnitus and the dorsal cochlear nucleus hypothesis. Am. J. Otolaryngol. 20:351–362.

    Article  PubMed  CAS  Google Scholar 

  • Lomholt, J. F., Keeling, J. W., Hansen, B. F., Ono, T., Stoltze, K., and Kjaer, I. (2003). The prenatal development of the human cerebellar field in Down syndrome. Orthod. Craniofac. Res. 6:220–226.

    Article  PubMed  CAS  Google Scholar 

  • Marini, A. M., Strauss, K. I., and Jacobowitz, D. M. (1997). Calretinin-containing neurons in rat cerebellar granule cell cultures. Brain Res. Bull. 42:279–288.

    Article  PubMed  CAS  Google Scholar 

  • Mazzoni, D. S., Ackley, R. S., and Nash, D. J. (1994). Abnormal pinna type and hearing loss correlations in Down’s syndrome. J. Intellect. Disabil. Res. 38(Pt 6):549–560.

    PubMed  Google Scholar 

  • Mugnaini, E., Dino, M. R., and Jaarsma, D. (1997). The unipolar brush cells of the mammalian cerebellum and cochlear nucleus: cytology and microcircuitry. Prog. Brain Res. 114:131–150.

    Article  PubMed  CAS  Google Scholar 

  • Mugnaini, E., and Floris, A. (1994). The unipolar brush cell: a neglected neuron of the mammalian cerebellar cortex. J. Comp. Neurol. 339:174–180.

    Article  PubMed  CAS  Google Scholar 

  • Nunzi, M. G., and Mugnaini, E. (2000). Unipolar brush cell axons form a large system of intrinsic mossy fibers in the postnatal vestibulocerebellum. J. Comp. Neurol. 422:55–65.

    Article  PubMed  CAS  Google Scholar 

  • Nunzi, M. G., Shigemoto, R., and Mugnaini, E. (2002). Differential expression of calretinin and metabotropic glutamate receptor mGluR1alpha defines subsets of unipolar brush cells in mouse cerebellum. J. Comp. Neurol. 451:189–199.

    Article  PubMed  CAS  Google Scholar 

  • Oertel, D., and Young, E. D. (2004). What’s a cerebellar circuit doing in the auditory system? Trends Neurosci. 27:104–110.

    Article  PubMed  CAS  Google Scholar 

  • Pinter, J. D., Eliez, S., Schmitt, J. E., Capone, G. T., and Reiss, A. L. (2001). Neuroanatomy of Down’s syndrome: A high-resolution MRI study. Am. J. Psychiatry 158:1659–1665.

    Article  PubMed  CAS  Google Scholar 

  • Rogers, J. H. (1989). Immunoreactivity for calretinin and other calcium-binding proteins in cerebellum. Neuroscience 31:711–721.

    Article  PubMed  CAS  Google Scholar 

  • Roper, R. J., Baxter, L. L., Saran, N. G., Klinedinst, D. K., Beachy, P. A., and Reeves, R. H. (2006) Defective cerebellar response to mitogenic Hedgehog signaling in Down’s syndrome mice. Proc. Natl. Acad. Sci. USA 103(5):1452–6.

    Article  PubMed  CAS  Google Scholar 

  • Rossi, D. J., Alford, S., Mugnaini, E., and Slater, N. T. (1995). Properties of transmission at a giant glutamatergic synapse in cerebellum: the mossy fiber-unipolar brush cell synapse. J. Neurophysiol. 74:24–42.

    PubMed  CAS  Google Scholar 

  • Saran, N. G., Pletcher, M. T., Natale, J. E., Cheng, Y., and Reeves, R. H. (2003). Global disruption of the cerebellar transcriptome in a Down syndrome mouse model. Hum. Mol. Genet. 12:2013–2019.

    Article  PubMed  CAS  Google Scholar 

  • Schmahmann, J. D., and Sherman, J. C. (1998). The cerebellar cognitive affective syndrome. Brain 121(Pt 4):561–579.

    Article  PubMed  Google Scholar 

  • Shumway-Cook, A., Woollacott, M. H. (1985). Dynamics of postural control in the child with Down syndrome. Phys. Ther. 65:1315–1322.

    PubMed  CAS  Google Scholar 

  • Siarey, R. J., Carlson, E. J., Epstein, C. J., Balbo, A., Rapoport, S. I., and Galdzicki, Z. (1999). Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology 38:1917–1920.

    Article  PubMed  CAS  Google Scholar 

  • Siarey, R. J., Stoll, J., Rapoport, S. I., and Galdzicki, Z. (1997). Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome. Neuropharmacology 36:1549–1554.

    Google Scholar 

  • Signorini, S., Liao, Y. J., Duncan, S. A., Jan, L. Y., and Stoffel, M. (1997). Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2. Proc. Natl. Acad. Sci. USA 94:923–927.

    Article  PubMed  CAS  Google Scholar 

  • Spano, M., Mercuri, E., Rando, T., Panto, T., Gagliano, A., Henderson, S., and Guzzetta, F. (1999). Motor and perceptual-motor competence in children with Down syndrome: variation in performance with age. Eur. J. Paediatr. Neurol. 3:7–13.

    Article  PubMed  CAS  Google Scholar 

  • Strovel, J., Stamberg, J., and Yarowsky, P. J. (1999). Interphase FISH for rapid identification of a down syndrome animal model. Cytogenet. Cell Genet. 86:285–287.

    Article  PubMed  CAS  Google Scholar 

  • Takacs, J., Borostyankoi, Z. A., Veisenberger, E., Vastagh, C., Vig, J., Gorcs, T. J., and Hamori, J. (2000). Postnatal development of unipolar brush cells in the cerebellar cortex of cat. J. Neurosci. Res. 61:107–115.

    Article  PubMed  CAS  Google Scholar 

  • Wickman, K., Nemec, J., Gendler, S. J., and Clapham, D. E. (1998). Abnormal heart rate regulation in GIRK4 knockout mice. Neuron 20:103–114.

    Article  PubMed  CAS  Google Scholar 

  • Winsky, L., Nakata, H., Martin, B. M., and Jacobowitz, D. M. (1989). Isolation, partial amino acid sequence, and immunohistochemical localization of a brain-specific calcium-binding protein. Proc. Natl. Acad Sci. USA 86:10139–10143.

    Article  PubMed  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, School of Medicine, Bethesda, Maryland, 20814, USA

    Chie Harashima, David M. Jacobowitz, Richard J. Siarey & Zygmunt Galdzicki

  2. Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA

    David M. Jacobowitz

  3. Laboratory of Metabolic Diseases and Molecular Cell Biology, Rockefeller University, New York, USA

    Markus Stoffel

  4. Center for Neuroscience Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC, USA

    Lina Chakrabarti & Tarik F. Haydar

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  1. Chie Harashima
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  2. David M. Jacobowitz
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  3. Markus Stoffel
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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, 717–732 (2006). https://doi.org/10.1007/s10571-006-9066-4

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