Neurogenetics

, 9:237 | Cite as

Behavioral effects of a deletion in Kcnn2, the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channels

  • Marek Szatanik
  • Nicolas Vibert
  • Isabelle Vassias
  • Jean-Louis Guénet
  • Daniel Eugène
  • Catherine de Waele
  • Jean Jaubert
Original Article

Abstract

Small-conductance Ca2+-activated potassium (SK) channels are heteromeric complexes of SK α-subunits and calmodulin that modulate membrane excitability, are responsible for part of the after-hyperpolarization (AHP) following action potentials, and thus control the firing patterns and excitability of most central neurons. An engineered knockout allele for the SK2 subunit has previously been reported. The hippocampal neurons of these mice lacked the medium latency component of the AHP, but the animals were not described as presenting any overt behavioral phenotype. In this report, we describe a deletion in the 5′ region of the Kcnn2 gene encoding the SK2 subunit in the mouse neurological frissonnant (fri) mutant. The frissonnant mutant phenotype is characterized by constant rapid tremor and locomotor instability. It has been suggested, based merely on its phenotype, as a potential model for human Parkinson disease. We used a positional cloning strategy to identify the mutation underlying the frissonnant phenotype. We narrowed the genetic disease interval and identified a 3,441-bp deletion in the Kcnn2 gene, one of the three candidate genes present in the interval. Expression studies showed complete absence of normal Kcnn2 transcripts while some tissue-specific abnormal truncated variants were detected. Intracellular electrophysiological recordings of central vestibular neurons revealed permanent alterations of the AHP and firing behavior that might cause the tremor and associated locomotor deficits. Thus, the fri mutation suggests a new, potentially important physiological role, which had not been described, for the SK2 subunit of small-conductance Ca2+-activated potassium channels.

Keywords

Frissonnant mouse mutant Genetic crosses Mutation identification SK2 channels Medial vestibular nucleus 

Supplementary material

(AVI 5.16 MB)

References

  1. 1.
    Bond CT, Maylie J, Adelman JP (2005) SK channels in excitability, pacemaking and synaptic integration. Curr Opin Neurobiol 15:305–311, doi:10.1016/j.conb.2005.05.001 PubMedCrossRefGoogle Scholar
  2. 2.
    Maylie J, Bond CT, Herson PS, Lee W-S, Adelman JP (2003) Small conductance Ca2+-activated K+ channels and calmodulin. J Physiol 554:255–261, doi:10.1113/jphysiol.2003.049072 PubMedCrossRefGoogle Scholar
  3. 3.
    Ji H, Shepard PD (2006) SK Ca2+-activated K+ channel ligands alter the firing pattern of dopamine-containing neurons in vivo. Neuroscience 140:623–633, doi:10.1016/j.neuroscience.2006.02.020 PubMedCrossRefGoogle Scholar
  4. 4.
    de Waele C, Serafin M, Khateb A, Yabe T, Vidal PP, Muhlethaler M (1993) Medial vestibular nucleus in the guinea-pig: apamin-induced rhythmic burst firing–an in vitro and in vivo study. Exp Brain Res 95:213–222, doi:10.1007/BF00229780 PubMedCrossRefGoogle Scholar
  5. 5.
    Johnston AR, MacLeod NK, Dutia MB (1994) Ionic conductances contributing to spike repolarization and after-potentials in rat medial vestibular nucleus neurones. J Physiol 481(Pt 1):61–77PubMedGoogle Scholar
  6. 6.
    Serafin M, de Waele C, Khateb A, Vidal PP, Muhlethaler M (1991) Medial vestibular nucleus in the guinea-pig. II. Ionic basis of the intrinsic membrane properties in brainstem slices. Exp Brain Res 84:426–433PubMedCrossRefGoogle Scholar
  7. 7.
    Straka H, Vibert N, Vidal PP, Moore LE, Dutia MB (2005) Intrinsic membrane properties of vertebrate vestibular neurons: function, development and plasticity. Prog Neurobiol 76:349–392, doi:10.1016/j.pneurobio.2005.10.002 PubMedCrossRefGoogle Scholar
  8. 8.
    Sailer CA, Hu H, Kaufmann WA, Trieb M, Schwarzer C, Storm JF et al (2002) Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain. J Neurosci 22:9698–9707PubMedGoogle Scholar
  9. 9.
    Sailer CA, Kaufmann WA, Marksteiner J, Knaus HG (2004) Comparative immunohistochemical distribution of three small-conductance Ca2+-activated potassium channel subunits, SK1, SK2, and SK3 in mouse brain. Mol Cell Neurosci 26:458–469, doi:10.1016/j.mcn.2004.03.002 PubMedCrossRefGoogle Scholar
  10. 10.
    Patko T, Vassias I, Vidal PP, De Waele C (2003) Modulation of the voltage-gated sodium- and calcium-dependent potassium channels in rat vestibular and facial nuclei after unilateral labyrinthectomy and facial nerve transection: an in situ hybridization study. Neuroscience 117:265–280, doi:10.1016/S0306-4522(02)00829-1 PubMedCrossRefGoogle Scholar
  11. 11.
    Bond CT, Herson PS, Strassmaier T, Hammond R, Stackman R, Maylie J et al (2004) Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent after hyperpolarization currents. J Neurosci 24:5301–5306, doi:10.1523/JNEUROSCI.0182-04.2004 PubMedCrossRefGoogle Scholar
  12. 12.
    Bond CT, Sprengel R, Bissonnette JM, Kaufmann WA, Pribnow D, Neelands T et al (2000) Respiration and parturition affected by conditional overexpression of the Ca2+-activated K+ channel subunit, SK3. Science 289:1942–1946, doi:10.1126/science.289.5486.1942 PubMedCrossRefGoogle Scholar
  13. 13.
    Callizot N, Guénet J-L, Baillet C, Warter J-M, Poindron P (2001) The frissonnant mutant mouse, a model of dopamine-sensitive, inherited motor syndrome. Neurobiol Dis 8:447–458, doi:10.1006/nbdi.2001.0393 PubMedCrossRefGoogle Scholar
  14. 14.
    Slesinger PA, Patil N, Liao YJ, Jan YN, Jan LY, Cox DR (1996) Functional effects of the mouse weaver mutation on G protein-gated inwardly rectifying K+ channels. Neuron 16:321–331, doi:10.1016/S0896-6273(00)80050-1 PubMedCrossRefGoogle Scholar
  15. 15.
    Bandmann O, Davis MB, Marsden CD, Wood NW (1996) The human homologue of the weaver mouse gene in familial and sporadic Parkinson’s disease. Neuroscience 72:877–879, doi:10.1016/0306-4522(96)00091-7 PubMedCrossRefGoogle Scholar
  16. 16.
    Vibert N, De Waele C, Serafin M, Babalian A, Muhlethaler M, Vidal PP (1997) The vestibular system as a model of sensorimotor transformations. A combined in vivo and in vitro approach to study the cellular mechanisms of gaze and posture stabilization in mammals. Prog Neurobiol 51:243–286, doi:10.1016/S0301-0082(96)00057-3 PubMedCrossRefGoogle Scholar
  17. 17.
    Eugene D, Deforges S, Guimont F, Idoux E, Vidal PP, Moore LE et al (2007) Developmental regulation of the membrane properties of central vestibular neurons by sensory vestibular information in the mouse. J Physiol 583:923–943, doi:10.1113/jphysiol.2007.133710 PubMedCrossRefGoogle Scholar
  18. 18.
    Beraneck M, Hachemaoui M, Idoux E, Ris L, Uno A, Godaux E et al (2003) Long-term plasticity of ipsilesional medial vestibular nucleus neurons after unilateral labyrinthectomy. J Neurophysiol 90:184–203, doi:10.1152/jn.01140.2002 PubMedCrossRefGoogle Scholar
  19. 19.
    Stocker M, Pedarzani P (2000) Differential distribution of three Ca(2+)-activated K(+) channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system. Mol Cell Neurosci 15:476–493, doi:10.1006/mcne.2000.0842 PubMedCrossRefGoogle Scholar
  20. 20.
    Chen MX, Gorman SA, Benson B, Singh K, Hieble JP, Michel MC et al (2004) Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum. Naunyn Schmiedebergs Arch Pharmacol 369:602–615, doi:10.1007/s00210-004-0934-5 PubMedCrossRefGoogle Scholar
  21. 21.
    Feranchak AP, Doctor RB, Troetsch M, Brookman K, Johnson SM, Fitz JG (2004) Calcium-dependent regulation of secretion in biliary epithelial cells: the role of apamin-sensitive SK channels. Gastroenterology 127:903–913, doi:10.1053/j.gastro.2004.06.047 PubMedCrossRefGoogle Scholar
  22. 22.
    Strassmaier T, Bond CT, Sailer CA, Knaus HG, Maylie J, Adelman JP (2005) A novel isoform of SK2 assembles with other SK subunits in mouse brain. J Biol Chem 280:21231–21236, doi:10.1074/jbc.M413125200 PubMedCrossRefGoogle Scholar
  23. 23.
    Schwenk F, Baron U, Rajewsky K (1995) A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res 23:5080–5081, doi:10.1093/nar/23.24.5080 PubMedCrossRefGoogle Scholar
  24. 24.
    Shmukler BE, Bond CT, Wilhelm S, Bruening-Wright A, Maylie J, Adelman JP et al (2001) Structure and complex transcription pattern of the mouse SK1 K(Ca) channel gene, KCNN1. Biochim Biophys Acta 1518:36–46PubMedGoogle Scholar
  25. 25.
    Blank T, Nijholt I, Kye M-J, Radulovic J, Spiess J (2003) Small-conductance, Ca2+-activated K+ channel SK3 generates age-related memory and LTP deficits. Nat Neurosci 6:911–912, doi:10.1038/nn1101 PubMedCrossRefGoogle Scholar
  26. 26.
    Hammond RS, Bond CT, Strassmaier T, Ngo-Anh TJ, Adelman JP, Maylie J et al (2006) Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity. J Neurosci 26:1844–1853, doi:10.1523/JNEUROSCI.4106-05.2006 PubMedCrossRefGoogle Scholar
  27. 27.
    Deschaux O, Bizot JC (2005) Apamin produces selective improvements of learning in rats. Neurosci Lett 386:5–8, doi:10.1016/j.neulet.2005.05.050 PubMedCrossRefGoogle Scholar
  28. 28.
    Mpari B, Regaya I, Escoffier G, Mourre C (2005) Differential effects of two blockers of small conductance Ca2+-activated K+ channels, apamin and lei-Dab7, on learning and memory in rats. J Integr Neurosci 4:381–396, doi:10.1142/S0219635205000884 PubMedCrossRefGoogle Scholar
  29. 29.
    Lallement G, Fosbraey P, Baille-Le-Crom V, Tattersall JE, Blanchet G, Wetherell JR et al (1995) Compared toxicity of the potassium channel blockers, apamin and dendrotoxin. Toxicology 104:47–52, doi:10.1016/0300-483X(95)03120-5 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Marek Szatanik
    • 1
  • Nicolas Vibert
    • 2
  • Isabelle Vassias
    • 2
  • Jean-Louis Guénet
    • 3
  • Daniel Eugène
    • 2
  • Catherine de Waele
    • 2
  • Jean Jaubert
    • 1
  1. 1.Unité de Génétique Fonctionnelle de la SourisInstitut PasteurParisFrance
  2. 2.Laboratoire de Neurobiologie des Réseaux SensorimoteursUniversité Paris Descartes, CNRS UMR 7060, Centre Universitaire des Saints-PèresParisFrance
  3. 3.Département de Biologie du DéveloppementInstitut PasteurParisFrance

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