K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration


Phasic activation of the dopamine (DA) midbrain system in response to unexpected reward or novelty is critical for adaptive behavioral strategies. This activation of DA midbrain neurons occurs via a synaptically triggered switch from low-frequency background spiking to transient high-frequency burst firing. We found that, in medial DA neurons of the substantia nigra (SN), activity of ATP-sensitive potassium (K-ATP) channels enabled NMDA-mediated bursting in vitro as well as spontaneous in vivo burst firing in anesthetized mice. Cell-selective silencing of K-ATP channel activity in medial SN DA neurons revealed that their K-ATP channel–gated burst firing was crucial for novelty-dependent exploratory behavior. We also detected a transcriptional upregulation of K-ATP channel and NMDA receptor subunits, as well as high in vivo burst firing, in surviving SN DA neurons from Parkinson's disease patients, suggesting that burst-gating K-ATP channel function in DA neurons affects phenotypes in both disease and health.

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Figure 1: In vivo firing characteristics and differences of burst properties of identified DA neurons in the SN and VTA.
Figure 2: K-ATP channels selectively control in vivo burst firing in m-SN DA neurons.
Figure 3: Co-activation of K-ATP channels and NMDA receptors is sufficient to induce bursting in vitro.
Figure 4: K-ATP channel activation shifts maximal firing frequencies induced by current injection into the burst range in m-SN DA neurons in vitro.
Figure 5: Virus-mediated expression of dominant-negative Kir6.2 pore mutant induced selective functional silencing of K-ATP channels in SN DA neurons.
Figure 6: Cell-selective silencing of K-ATP channels in SN DA neurons using virally mediated gene transfer is sufficient to prevent burst firing in m-SN neurons.
Figure 7: K-ATP channels in m-SN DA neurons are necessary for novelty-dependent exploratory behavior.
Figure 8: Increased mRNA levels of the K-ATP channel subunit SUR1 and high burst firing in SN DA neurons from Parkinson's disease patients.


  1. 1

    Bromberg-Martin, E.S., Matsumoto, M. & Hikosaka, O. Dopamine in motivational control: rewarding, aversive and alerting. Neuron 68, 815–834 (2010).

  2. 2

    Schultz, W. Multiple dopamine functions at different time courses. Annu. Rev. Neurosci. 30, 259–288 (2007).

  3. 3

    Lammel, S. et al. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57, 760–773 (2008).

  4. 4

    Lammel, S., Ion, D.I., Roeper, J. & Malenka, R.C. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70, 855–862 (2011).

  5. 5

    Krebs, R.M., Heipertz, D., Schuetze, H. & Duzel, E. Novelty increases the mesolimbic functional connectivity of the substantia nigra/ventral tegmental area (SN/VTA) during reward anticipation: Evidence from high-resolution fMRI. Neuroimage 58, 647–655 (2011).

  6. 6

    Jin, X. & Costa, R.M. Start/stop signals emerge in nigrostriatal circuits during sequence learning. Nature 466, 457–462 (2010).

  7. 7

    Zweifel, L.S. et al. Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior. Proc. Natl. Acad. Sci. USA 106, 7281–7288 (2009).

  8. 8

    Brazhnik, E., Shah, F. & Tepper, J.M. GABAergic afferents activate both GABAA and GABAB receptors in mouse substantia nigra dopaminergic neurons in vivo. J. Neurosci. 28, 10386–10398 (2008).

  9. 9

    Johnson, S.W., Seutin, V. & North, R.A. Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump. Science 258, 665–667 (1992).

  10. 10

    Shen, K.Z. & Johnson, S.W. Ca2+ influx through NMDA-gated channels activates ATP-sensitive K+ currents through a nitric oxide-cGMP pathway in subthalamic neurons. J. Neurosci. 30, 1882–1893 (2010).

  11. 11

    Gomis, A. & Valdeolmillos, M. Regulation by tolbutamide and diazoxide of the electrical activity in mouse pancreatic beta-cells recorded in vivo. Br. J. Pharmacol. 123, 443–448 (1998).

  12. 12

    Fridlyand, L.E., Tamarina, N. & Philipson, L.H. Bursting and calcium oscillations in pancreatic beta-cells: specific pacemakers for specific mechanisms. Am. J. Physiol. Endocrinol. Metab. 299, E517–E532 (2010).

  13. 13

    Liss, B., Bruns, R. & Roeper, J. Alternative sulfonylurea receptor expression defines metabolic sensitivity of K-ATP channels in dopaminergic midbrain neurons. EMBO J. 18, 833–846 (1999).

  14. 14

    Liss, B. et al. K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat. Neurosci. 8, 1742–1751 (2005).

  15. 15

    Chan, C.S. et al. 'Rejuvenation' protects neurons in mouse models of Parkinson's disease. Nature 447, 1081–1086 (2007).

  16. 16

    Yamada, T., McGeer, P.L., Baimbridge, K.G. & McGeer, E.G. Relative sparing in Parkinson's disease of substantia nigra dopamine neurons containing calbindin-D28K. Brain Res. 526, 303–307 (1990).

  17. 17

    Grace, A.A. & Bunney, B.S. The control of firing pattern in nigral dopamine neurons: burst firing. J. Neurosci. 4, 2877–2890 (1984).

  18. 18

    Wilson, C.J., Young, S.J. & Groves, P.M. Statistical properties of neuronal spike trains in the substantia nigra: cell types and their interactions. Brain Res. 136, 243–260 (1977).

  19. 19

    Bingmer, M., Schiemann, J., Roeper, J. & Schneider, G. Measuring burstiness and regularity in oscillatory spike trains. J. Neurosci. Methods 201, 426–437 (2011).

  20. 20

    Yamada, K. et al. Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science 292, 1543–1546 (2001).

  21. 21

    Dabrowski, M., Larsen, T., Ashcroft, F.M., Bondo Hansen, J. & Wahl, P. Potent and selective activation of the pancreatic beta-cell type K(ATP) channel by two novel diazoxide analogues. Diabetologia 46, 1375–1382 (2003).

  22. 22

    Zerangue, N., Schwappach, B., Jan, Y.N. & Jan, L.Y. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Neuron 22, 537–548 (1999).

  23. 23

    Bayer, H.M., Lau, B. & Glimcher, P.W. Statistics of midbrain dopamine neuron spike trains in the awake primate. J. Neurophysiol. 98, 1428–1439 (2007).

  24. 24

    Hyland, B.I., Reynolds, J.N., Hay, J., Perk, C.G. & Miller, R. Firing modes of midbrain dopamine cells in the freely moving rat. Neuroscience 114, 475–492 (2002).

  25. 25

    Deacon, R.M. et al. Behavioral phenotyping of mice lacking the K ATP channel subunit Kir6.2. Physiol. Behav. 87, 723–733 (2006).

  26. 26

    Gründemann, J., Schlaudraff, F., Haeckel, O. & Liss, B. Elevated alpha-synuclein mRNA levels in individual UV-laser-microdissected dopaminergic substantia nigra neurons in idiopathic Parkinson's disease. Nucleic Acids Res. 36, e38 (2008).

  27. 27

    Zaghloul, K.A. et al. Human substantia nigra neurons encode unexpected financial rewards. Science 323, 1496–1499 (2009).

  28. 28

    Nichols, C.G. KATP channels as molecular sensors of cellular metabolism. Nature 440, 470–476 (2006).

  29. 29

    Geng, X. et al. {alpha}-Synuclein binds the KATP channel at insulin-secretory granules and inhibits insulin secretion. Am. J. Physiol. Endocrinol. Metab. 300, E276–E286 (2011).

  30. 30

    Deister, C.A., Teagarden, M.A., Wilson, C.J. & Paladini, C.A. An intrinsic neuronal oscillator underlies dopaminergic neuron bursting. J. Neurosci. 29, 15888–15897 (2009).

  31. 31

    Johnson, S.W., Mercuri, N.B. & North, R.A. 5-hydroxytryptamine1B receptors block the GABAB synaptic potential in rat dopamine neurons. J. Neurosci. 12, 2000–2006 (1992).

  32. 32

    Parker, J.G., Beutler, L.R. & Palmiter, R.D. The contribution of NMDA receptor signaling in the corticobasal ganglia reward network to appetitive Pavlovian learning. J. Neurosci. 31, 11362–11369 (2011).

  33. 33

    Mameli-Engvall, M. et al. Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron 50, 911–921 (2006).

  34. 34

    Harnett, M.T., Bernier, B.E., Ahn, K.C. & Morikawa, H. Burst timing–dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons. Neuron 62, 826–838 (2009).

  35. 35

    Herrik, K.F., Christophersen, P. & Shepard, P.D. Pharmacological modulation of the gating properties of small conductance Ca2+-activated K+ channels alters the firing pattern of dopamine neurons in vivo. J. Neurophysiol. 104, 1726–1735 (2010).

  36. 36

    Opland, D.M., Leinninger, G.M. & Myers, M.G. Jr. Modulation of the mesolimbic dopamine system by leptin. Brain Res. 1350, 65–70 (2010).

  37. 37

    Andrews, Z.B. et al. Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J. Neurosci. 29, 14057–14065 (2009).

  38. 38

    Haber, S.N. & Knutson, B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35, 4–26 (2010).

  39. 39

    Kravitz, A.V. et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466, 622–626 (2010).

  40. 40

    Lex, B. & Hauber, W. The role of dopamine in the prelimbic cortex and the dorsomedial striatum in instrumental conditioning. Cereb. Cortex 20, 873–883 (2010).

  41. 41

    Lex, B. & Hauber, W. Disconnection of the entorhinal cortex and dorsomedial striatum impairs the sensitivity to instrumental contingency degradation. Neuropsychopharmacology 35, 1788–1796 (2010).

  42. 42

    Lisman, J.E. & Grace, A.A. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 46, 703–713 (2005).

  43. 43

    Bunzeck, N. & Duzel, E. Absolute coding of stimulus novelty in the human substantia nigra/VTA. Neuron 51, 369–379 (2006).

  44. 44

    Bódi, N. et al. Reward-learning and the novelty-seeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson's patients. Brain 132, 2385–2395 (2009).

  45. 45

    Rutledge, R.B. et al. Dopaminergic drugs modulate learning rates and perseveration in Parkinson's patients in a dynamic foraging task. J. Neurosci. 29, 15104–15114 (2009).

  46. 46

    Guzman, J.N. et al. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468, 696–700 (2010).

  47. 47

    Ungless, M.A., Magill, P.J. & Bolam, J.P. Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science 303, 2040–2042 (2004).

  48. 48

    Franklin, K. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates (Elsevier, 2001).

  49. 49

    Brown, M.T., Henny, P., Bolam, J.P. & Magill, P.J. Activity of neurochemically heterogeneous dopaminergic neurons in the substantia nigra during spontaneous and driven changes in brain state. J. Neurosci. 29, 2915–2925 (2009).

  50. 50

    Pinault, D. A novel single-cell staining procedure performed in vivo under electrophysiological control: morpho-functional features of juxtacellularly labeled thalamic cells and other central neurons with biocytin or Neurobiotin. J. Neurosci. Methods 65, 113–136 (1996).

  51. 51

    Zhang, D., Yang, S., Jin, G.Z., Bunney, B.S. & Shi, W.X. Oscillatory firing of dopamine neurons: differences between cells in the substantia nigra and ventral tegmental area. Synapse 62, 169–175 (2008).

  52. 52

    Miki, T. et al. Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel. Proc. Natl. Acad. Sci. USA 94, 11969–11973 (1997).

  53. 53

    Burger, C. et al. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2 and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol. Ther. 10, 302–317 (2004).

  54. 54

    Henny, P. et al. Structural correlates of heterogeneous in vivo activity of midbrain dopaminergic neurons. Nat. Neurosci. 15, 613–619 (2012).

  55. 55

    Martín-Ibañez, R. et al. Vesicular glutamate transporter 3 (VGLUT3) identifies spatially segregated excitatory terminals in the rat substantia nigra. Eur. J. Neurosci. 23, 1063–1070 (2006).

  56. 56

    Ulusoy, A., Sahin, G., Bjorklund, T., Aebischer, P. & Kirik, D. Dose optimization for long-term rAAV-mediated RNA interference in the nigrostriatal projection neurons. Mol. Ther. 17, 1574–1584 (2009).

  57. 57

    Gründemann, J., Schlaudraff, F. & Liss, B. UV-laser microdissection and mRNA expression analysis of individual neurons from postmortem Parkinson's disease brains. Methods Mol. Biol. 755, 363–374 (2011).

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We thank S. Petzoldt, H. Schalk and A. Parg for assistance in immunohistochemistry, and M. Fauler for mRNA expression data analysis. The study was supported by Gemeinnützige Hertiestiftung (J.R. and B.L.), SFB815 (J.R.), SFB497 (B.L.), BMBF Nationales Genomforschungsnetzwerk NGFN-II/plus (01GS08134, J.R. and B.L.), Alfried Krupp prize (B.L.), LOEWE-Schwerpunkt Neuronale Koordination Forschungsschwerpunkt Frankfurt NeFF (J.R. and G.S.), Bernstein Fokus Neurotechnology Frankfurt (G.S. and M.B.), doctoral fellowship Studienstiftung des deutschen Volkes (J.S.) and Medical Research Council UK (U138197109, P.J.M.).

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J.S. carried out in vivo electrophysiology, juxtacellular labeling (training by P.J.M.), viral gene transfer, retrograde tracing, immunocytochemistry, microscopy and data analyses. V.K. and J.S. carried out animal behavior experiments. J.R. performed in vitro electrophysiology. The GLO model was designed by M.B. and G.S. F.S. and B.L. carried out laser microdissection and molecular biology. S.S. generated Kir6.2−/−. K.A.Z. performed human SN recordings. J.S., P.J.M., B.L. and J.R. designed the study and wrote the manuscript.

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Correspondence to Birgit Liss or Jochen Roeper.

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Schiemann, J., Schlaudraff, F., Klose, V. et al. K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration. Nat Neurosci 15, 1272–1280 (2012). https://doi.org/10.1038/nn.3185

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