DOI QR코드

DOI QR Code

Somatodendritic organization of pacemaker activity in midbrain dopamine neurons

  • Jinyoung Jang (Department of Physiology, Sungkyunkwan University School of Medicine) ;
  • Shin Hye Kim (Department of Physiology, Sungkyunkwan University School of Medicine) ;
  • Ki Bum Um (Department of Physiology, Sungkyunkwan University School of Medicine) ;
  • Hyun Jin Kim (Department of Physiology, Sungkyunkwan University School of Medicine) ;
  • Myoung Kyu Park (Department of Physiology, Sungkyunkwan University School of Medicine)
  • Received : 2023.12.21
  • Accepted : 2024.01.08
  • Published : 2024.03.01

Abstract

The slow and regular pacemaking activity of midbrain dopamine (DA) neurons requires proper spatial organization of the excitable elements between the soma and dendritic compartments, but the somatodendritic organization is not clear. Here, we show that the dynamic interaction between the soma and multiple proximal dendritic compartments (PDCs) generates the slow pacemaking activity in DA neurons. In multipolar DA neurons, spontaneous action potentials (sAPs) consistently originate from the axon-bearing dendrite. However, when the axon initial segment was disabled, sAPs emerge randomly from various primary PDCs, indicating that multiple PDCs drive pacemaking. Ca2+ measurements and local stimulation/perturbation experiments suggest that the soma serves as a stably-oscillating inertial compartment, while multiple PDCs exhibit stochastic fluctuations and high excitability. Despite the stochastic and excitable nature of PDCs, their activities are balanced by the large centrally-connected inertial soma, resulting in the slow synchronized pacemaking rhythm. Furthermore, our electrophysiological experiments indicate that the soma and PDCs, with distinct characteristics, play different roles in glutamate-induced burst-pause firing patterns. Excitable PDCs mediate excitatory burst responses to glutamate, while the large inertial soma determines inhibitory pause responses to glutamate. Therefore, we could conclude that this somatodendritic organization serves as a common foundation for both pacemaker activity and evoked firing patterns in midbrain DA neurons.

Keywords

Acknowledgement

This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI13C1793) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2017R1A2B3005656 and 2022R1A2C2009159).

References

  1. Magee JC. Dendritic integration of excitatory synaptic input. Nat Rev Neurosci. 2000;1:181-190. https://doi.org/10.1038/35044552
  2. Stuart GJ, Spruston N. Dendritic integration: 60 years of progress. Nat Neurosci. 2015;18:1713-1721. https://doi.org/10.1038/nn.4157
  3. Grace AA, Bunney BS. Intracellular and extracellular electrophysiology of nigral dopaminergic neurons--1. Identification and characterization. Neuroscience. 1983;10:301-315. https://doi.org/10.1016/0306-4522(83)90135-5
  4. Grace AA, Bunney BS. Intracellular and extracellular electrophysiology of nigral dopaminergic neurons--2. Action potential generating mechanisms and morphological correlates. Neuroscience. 1983;10:317-331. https://doi.org/10.1016/0306-4522(83)90136-7
  5. Grace AA, Onn SP. Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro. J Neurosci. 1989;9:3463-3481. https://doi.org/10.1523/JNEUROSCI.09-10-03463.1989
  6. Cossette M, Lecomte F, Parent A. Morphology and distribution of dopaminergic neurons intrinsic to the human striatum. J Chem Neuroanat. 2005;29:1-11. https://doi.org/10.1016/j.jchemneu.2004.08.007
  7. Hausser M, Stuart G, Racca C, Sakmann B. Axonal initiation and active dendritic propagation of action potentials in substantia nigra neurons. Neuron. 1995;15:637-647. https://doi.org/10.1016/0896-6273(95)90152-3
  8. Gentet LJ, Williams SR. Dopamine gates action potential backpropagation in midbrain dopaminergic neurons. J Neurosci. 2007;27:1892-1901. https://doi.org/10.1523/JNEUROSCI.5234-06.2007
  9. Wilson CJ, Callaway JC. Coupled oscillator model of the dopaminergic neuron of the substantia nigra. J Neurophysiol. 2000;83:3084-3100. https://doi.org/10.1152/jn.2000.83.5.3084
  10. Kang Y, Kitai ST. Calcium spike underlying rhythmic firing in dopaminergic neurons of the rat substantia nigra. Neurosci Res. 1993;18:195-207. https://doi.org/10.1016/0168-0102(93)90055-U
  11. Guzman JN, Sanchez-Padilla J, Chan CS, Surmeier DJ. Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci. 2009;29:11011-11019. https://doi.org/10.1523/JNEUROSCI.2519-09.2009
  12. Blythe SN, Wokosin D, Atherton JF, Bevan MD. Cellular mechanisms underlying burst firing in substantia nigra dopamine neurons. J Neurosci. 2009;29:15531-15541. https://doi.org/10.1523/JNEUROSCI.2961-09.2009
  13. Gonzalez-Cabrera C, Meza R, Ulloa L, Merino-Sepulveda P, Luco V, Sanhueza A, Onate-Ponce A, Bolam JP, Henny P. Characterization of the axon initial segment of mice substantia nigra dopaminergic neurons. J Comp Neurol. 2017;525:3529-3542. https://doi.org/10.1002/cne.24288
  14. Jang J, Um KB, Jang M, Kim SH, Cho H, Chung S, Kim HJ, Park MK. Balance between the proximal dendritic compartment and the soma determines spontaneous firing rate in midbrain dopamine neurons. J Physiol. 2014;592:2829-2844. https://doi.org/10.1113/jphysiol.2014.275032
  15. Medvedev GS, Wilson CJ, Callaway JC, Kopell N. Dendritic synchrony and transient dynamics in a coupled oscillator model of the dopaminergic neuron. J Comput Neurosci. 2003;15:53-69. https://doi.org/10.1023/A:1024422802673
  16. Grace AA, Floresco SB, Goto Y, Lodge DJ. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci. 2007;30:220-227. https://doi.org/10.1016/j.tins.2007.03.003
  17. Pucak ML, Grace AA. Regulation of substantia nigra dopamine neurons. Crit Rev Neurobiol. 1994;9:67-89.
  18. Overton PG, Clark D. Burst firing in midbrain dopaminergic neurons. Brain Res Brain Res Rev. 1997;25:312-334. https://doi.org/10.1016/S0165-0173(97)00039-8
  19. Hyland BI, Reynolds JN, Hay J, Perk CG, Miller R. Firing modes of midbrain dopamine cells in the freely moving rat. Neuroscience. 2002;114:475-492. https://doi.org/10.1016/S0306-4522(02)00267-1
  20. Tsai HC, Zhang F, Adamantidis A, Stuber GD, Bonci A, de Lecea L, Deisseroth K. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science. 2009;324:1080-1084. https://doi.org/10.1126/science.1168878
  21. Wise RA. Roles for nigrostriatal--not just mesocorticolimbic--dopamine in reward and addiction. Trends Neurosci. 2009;32:517-524. https://doi.org/10.1016/j.tins.2009.06.004
  22. Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinson's disease. Science. 2003;302:819-822. https://doi.org/10.1126/science.1087753
  23. Surmeier DJ, Guzman JN, Sanchez J, Schumacker PT. Physiological phenotype and vulnerability in Parkinson's disease. Cold Spring Harb Perspect Med. 2012;2:a009290.
  24. Grace AA. In vivo and in vitro intracellular recordings from rat midbrain dopamine neurons. Ann N Y Acad Sci. 1988;537:51-76. https://doi.org/10.1111/j.1749-6632.1988.tb42096.x
  25. Um KB, Hahn S, Kim SW, Lee YJ, Birnbaumer L, Kim HJ, Park MK. TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons. Elife. 2021;10:e70920.
  26. Hahn S, Um KB, Kim SW, Kim HJ, Park MK. Proximal dendritic localization of NALCN channels underlies tonic and burst firing in nigral dopaminergic neurons. J Physiol. 2023;601:171-193. https://doi.org/10.1113/JP283716
  27. Jang M, Um KB, Jang J, Kim HJ, Cho H, Chung S, Park MK. Coexistence of glutamatergic spine synapses and shaft synapses in substantia nigra dopamine neurons. Sci Rep. 2015;5:14773.
  28. Choi YM, Kim SH, Uhm DY, Park MK. Glutamate-mediated [Ca2+] c dynamics in spontaneously firing dopamine neurons of the rat substantia nigra pars compacta. J Cell Sci. 2003;116:2665-2675. https://doi.org/10.1242/jcs.00481
  29. Hahn J, Tse TE, Levitan ES. Long-term K+ channel-mediated dampening of dopamine neuron excitability by the antipsychotic drug haloperidol. J Neurosci. 2003;23:10859-10866. https://doi.org/10.1523/JNEUROSCI.23-34-10859.2003
  30. Ping HX, Shepard PD. Blockade of SK-type Ca2+-activated K+ channels uncovers a Ca2+-dependent slow afterdepolarization in nigral dopamine neurons. J Neurophysiol. 1999;81:977-984. https://doi.org/10.1152/jn.1999.81.3.977
  31. Wolfart J, Roeper J. Selective coupling of T-type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons. J Neurosci. 2002;22:3404-3413. Erratum in: J Neurosci. 2002;22:5250.
  32. Wolfart J, Neuhoff H, Franz O, Roeper J. Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. J Neurosci. 2001;21:3443-3456. https://doi.org/10.1523/JNEUROSCI.21-10-03443.2001
  33. Deignan J, Lujan R, Bond C, Riegel A, Watanabe M, Williams JT, Maylie J, Adelman JP. SK2 and SK3 expression differentially affect firing frequency and precision in dopamine neurons. Neuroscience. 2012;217:67-76. https://doi.org/10.1016/j.neuroscience.2012.04.053
  34. Kuznetsov AS, Kopell NJ, Wilson CJ. Transient high-frequency firing in a coupled-oscillator model of the mesencephalic dopaminergic neuron. J Neurophysiol. 2006;95:932-947. https://doi.org/10.1152/jn.00691.2004
  35. Chuhma N, Zhang H, Masson J, Zhuang X, Sulzer D, Hen R, Rayport S. Dopamine neurons mediate a fast excitatory signal via their glutamatergic synapses. J Neurosci. 2004;24:972-981. https://doi.org/10.1523/JNEUROSCI.4317-03.2004
  36. Fiorillo CD, Williams JT. Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature. 1998;394:78-82. https://doi.org/10.1038/27919
  37. Kim SH, Choi YM, Chung S, Uhm DY, Park MK. Two different Ca2+-dependent inhibitory mechanisms of spontaneous firing by glutamate in dopamine neurons. J Neurochem. 2004;91:983-995. https://doi.org/10.1111/j.1471-4159.2004.02783.x
  38. Morikawa H, Imani F, Khodakhah K, Williams JT. Inositol 1,4,5-triphosphate-evoked responses in midbrain dopamine neurons. J Neurosci. 2000;20:RC103.
  39. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4:517-529. https://doi.org/10.1038/nrm1155
  40. Papaioannou VE, Verkerk AO, Amin AS, de Bakker JM. Intracardiac origin of heart rate variability, pacemaker funny current and their possible association with critical illness. Curr Cardiol Rev. 2013;9:82-96. https://doi.org/10.2174/1573403X11309010010
  41. Yaniv Y, Lyashkov AE, Sirenko S, Okamoto Y, Guiriba TR, Ziman BD, Morrell CH, Lakatta EG. Stochasticity intrinsic to coupledclock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells. J Mol Cell Cardiol. 2014;77:1-10. https://doi.org/10.1016/j.yjmcc.2014.09.008
  42. Anwar H, Hepburn I, Nedelescu H, Chen W, De Schutter E. Stochastic calcium mechanisms cause dendritic calcium spike variability. J Neurosci. 2013;33:15848-15867. https://doi.org/10.1523/JNEUROSCI.1722-13.2013
  43. Deister CA, Teagarden MA, Wilson CJ, Paladini CA. An intrinsic neuronal oscillator underlies dopaminergic neuron bursting. J Neurosci. 2009;29:15888-15897. https://doi.org/10.1523/JNEUROSCI.4053-09.2009
  44. Kuznetsova AY, Huertas MA, Kuznetsov AS, Paladini CA, Canavier CC. Regulation of firing frequency in a computational model of a midbrain dopaminergic neuron. J Comput Neurosci. 2010;28:389-403. https://doi.org/10.1007/s10827-010-0222-y
  45. Kole MH, Ilschner SU, Kampa BM, Williams SR, Ruben PC, Stuart GJ. Action potential generation requires a high sodium channel density in the axon initial segment. Nat Neurosci. 2008;11:178-186. https://doi.org/10.1038/nn2040
  46. Debanne D, Campanac E, Bialowas A, Carlier E, Alcaraz G. Axon physiology. Physiol Rev. 2011;91:555-602. https://doi.org/10.1152/physrev.00048.2009
  47. Tucker KR, Huertas MA, Horn JP, Canavier CC, Levitan ES. Pacemaker rate and depolarization block in nigral dopamine neurons: a somatic sodium channel balancing act. J Neurosci. 2012;32:14519-14531. https://doi.org/10.1523/JNEUROSCI.1251-12.2012
  48. Rall W, Burke RE, Holmes WR, Jack JJ, Redman SJ, Segev I. Matching dendritic neuron models to experimental data. Physiol Rev. 1992;72(4 Suppl):S159-S186. https://doi.org/10.1152/physrev.1992.72.suppl_4.S159
  49. Migliore M, Shepherd GM. Emerging rules for the distributions of active dendritic conductances. Nat Rev Neurosci. 2002;3:362-370. https://doi.org/10.1038/nrn810
  50. Amini B, Clark JW Jr, Canavier CC. Calcium dynamics underlying pacemaker-like and burst firing oscillations in midbrain dopaminergic neurons: a computational study. J Neurophysiol. 1999;82:2249-2261. https://doi.org/10.1152/jn.1999.82.5.2249
  51. Katayama J, Akaike N, Nabekura J. Characterization of pre- and post-synaptic metabotropic glutamate receptor-mediated inhibitory responses in substantia nigra dopamine neurons. Neurosci Res. 2003;45:101-115. https://doi.org/10.1016/S0168-0102(02)00202-X