Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Endocannabinoid signaling modulates neurons of the pedunculopontine nucleus (PPN) via astrocytes

Abstract

The pedunculopontine nucleus (PPN) is known as the cholinergic part of the reticular activating system (RAS) and it plays an important role in transitions of slow-wave sleep to REM sleep and wakefulness. Although both exogenous and endocannabinoids affect sleep, the mechanism of endocannabinoid neuromodulation has not been characterized at cellular level in the PPN. In this paper, we demonstrate that both neurons and glial cells from the PPN respond to cannabinoid type 1 (CB1) receptor agonists. The neuronal response can be depolarization or hyperpolarization, while astrocytes exhibit more frequent calcium waves. All these effects are absent in CB1 gene-deficient mice. Blockade of the fast synaptic neurotransmission or neuronal action potential firing does not change the effect on the neuronal membrane potential significantly, while inhibition of astrocytic calcium waves by thapsigargin diminishes the response. Inhibition of group I metabotropic glutamate receptors (mGluRs) abolishes hyperpolarization, whereas blockade of group II mGluRs prevents depolarization. Initially active neurons and glial cells display weaker responses partially due to the increased endocannabinoid tone in their environment. Taken together, we propose that cannabinoid receptor stimulation modulates PPN neuronal activity in the following manner: active neurons may elicit calcium waves in astrocytes via endogenous CB1 receptor agonists. Astrocytes in turn release glutamate that activates different metabotropic glutamate receptors of neurons and modulate PPN neuronal activity.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhäuser C, Pilati E, Volterra A (2004) Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7(6):613–620

  2. Bolla KI, Lesage SR, Gamaldo CE, Neubauer DN, Funderburk FR, Cadet JL, David PM, Verdejo-Garcia A, Benbrook AR (2008) Sleep disturbance in heavy marijuana users. Sleep 31(6):901–908

  3. Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y (2012) Endocannabinoid signaling and synaptic function. Neuron 76(1):70–81

  4. Chavis P, Shinozaki H, Bockaert J, Fagni L (1994) The metabotropic glutamate receptor types 2/3 inhibit L-type calcium channels via a pertussis toxin-sensitive G-protein in cultured cerebellar granule cells. J Neurosci 14(11 Pt 2):7067–7076

  5. Chavis P, Fagni L, Bockaert J, Lansman JB (1995) Modulation of calcium channels by metabotropic glutamate receptors in cerebellar granule cells. Neuropharmacology 34(8):929–937

  6. Coiret G, Ster J, Grewe B, Wendling F, Helmchen F, Gerber U, Benquet P (2012) Neuron to astrocyte communication via cannabinoid receptors is necessary for sustained epileptiform activity in rat hippocampus. PLoS ONE 7(5):e37320

  7. Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M (1998) Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci USA 95(26):15735–15740

  8. D’Antoni S, Berretta A, Bonaccorso CM, Bruno V, Aronica E, Nicoletti F, Catania MV (2008) Metabotropic glutamate receptors in glial cells. Neurochem Res 33(12):2436–2443

  9. D’Ascenzo M, Fellin T, Terunuma M, Revilla-Sanchez R, Meaney DF, Auberson YP, Moss SJ, Haydon PG (2007) mGluR5 stimulates gliotransmission in the nucleus accumbens. Proc Natl Acad Sci USA 104(6):1995–2000

  10. Díaz-Alonso J, Aguado T, de Salas-Quiroga A, Ortega Z, Guzmán M, Galve-Roperh I (2014) CB1 Cannabinoid Receptor-Dependent Activation of mTORC1/Pax6 Signaling Drives Tbr2 Expression and Basal Progenitor Expansion in the Developing Mouse Cortex. Cereb Cortex

  11. Duan S, Anderson CM, Keung EC, Chen Y, Chen Y, Swanson RA (2003) P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci 23(4):1320–1328

  12. Feinberg I, Jones R, Walker JM, Cavness C, March J (1975) Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clin Pharmacol Ther 17(49):458–466

  13. Fernández-Ruiz J, Pazos MR, García-Arencibia M, Sagredo O, Ramos JA (2008) Role of CB2 receptors in neuroprotective effects of cannabinoids. Mol Cell Endocrinol 286(1–2)Supplement 1:S91–S96

  14. Ferraguti F, Shigemoto R (2006) Metabotropic glutamate receptors. Cell Tissue Res 326(2):483–504

  15. Frank MG (2013) Astroglial regulation of sleep homeostasis. Curr Opin Neurobiol 23(5):812–818

  16. Garcia-Rill E (1991) The pedunculopontine nucleus. Prog Neurobiol 36:363–389

  17. Garcia-Rill E, Charlesworth A, Heister D, Ye M, Hayar A (2008) The developmental decrease in REM sleep: the role of transmitters and electrical coupling. Sleep 31(5):673–690

  18. Garcia-Rill E, Simon C, Smith K, Kezunovic N, Hyde J (2011) The pedunculopontine tegmental nucleus: from basic neuroscience to neurosurgical applications. J Neural Transm 118:1397–1407

  19. Han J, Kesner P, Metna-Laurent M, Duan T, Xu L, Georges F, Koehl M, Abrous DN, Mendizabal-Zubiaga J, Grandes P, Liu Q, Bai G, Wang W, Xiong L, Ren W, Marsicano G, Zhang X (2012) Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell 148(5):1039–1050

  20. Harata N, Katayama J, Takeshita Y, Murai Y, Akaike N (1996) Two components of metabotropic glutamate responses in acutely dissociated CA3 pyramidal neurons of the rat. Brain Res 711:223–233

  21. Hegyi Z, Kis G, Holló K, Ledent C, Antal M (2009) Neuronal and glial localization of the cannabinoid-1 receptor in the superficial spinal dorsal horn of the rodent spinal cord. Eur J Neurosci 30(2):251–262

  22. Hegyi Z, Holló K, Kis G, Mackie K, Antal M (2012) Differential distribution of diacylglycerol lipase-alpha and N-acylphosphatidylethanolamine-specific phospholipase d immunoreactivity in the superficial spinal dorsal horn of rats. Glia 60(9):1316–1329

  23. Hermes ML, Renaud LP (2011) Postsynaptic and presynaptic group II metabotropic glutamate receptor activation reduces neuronal excitability in rat midline paraventricular thalamic nucleus. J Pharmacol Exp Ther 336(3):840–849

  24. Herrera-Solís A, Vásquez KG, Prospéro-García O (2010) Acute and subchronic administration of anandamide or oleamide increases REM sleep in rats. Pharmacol Biochem Behav 95:106–112

  25. Hillard CJ, Manna S, Greenberg MJ, DiCamelli R, Ross RA, Stevenson LA, Murphy V, Pertwee RG, Campbell WB (1999) Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther 289(3):1427–1433

  26. Hubert GW (2004) Smith Y (2004) Age-related changes in the expression of axonal and glial group I metabotropic glutamate receptor in the rat substantia nigra pars reticulata. J Comp Neurol 475(1):95–106

  27. Irie T, Fukui I, Ohmori H (2006) Activation of GIRK channels by muscarinic receptors and group II metabotropic glutamate receptors suppresses Golgi cell activity in the cochlear nucleus of mice. J Neurophysiol 96(5):2633–2644

  28. Jenkinson N, Nandi D, Muthusamy K, Ray NJ, Gregory R, Stein JF, Aziz TZ (2009) Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus. Mov Disord 24(3):319–328

  29. Jian K, Cifelli P, Pignatelli A, Frigato E, Belluzzi O (2010) Metabotropic glutamate receptors 1 and 5 differentially regulate bulbar dopaminergic cell function. Brain Res 1354:47–63

  30. Kato HK, Kassai H, Watabe AM, Aiba A, Manabe T (2012) Functional coupling of the metabotropic glutamate receptor, InsP3 receptor and L-type Ca2+ channel in mouse CA1 pyramidal cells. J Physiol 590(Pt 13):3019–3034

  31. Katona I, Freund TF (2012) Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci 35:529–558

  32. Katona I, Sperlágh B, Sík A, Kőfalvi A, Vizi ES, Mackie K, Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558

  33. Kawamura Y, Fukaya M, Maejima T, Yoshida T, Miura E, Watanabe M, Ohno-Shosaku T, Kano M (2006) The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci 26:2991–3001

  34. Knoflach F, Kemp JA (1998) Metabotropic glutamate group II receptors activate a G protein-coupled inwardly rectifying K+ current in neurones of the rat cerebellum. J Physiol 509(Pt 2):347–354

  35. Kohlmeier KA, Christensen MH, Kristensen MP, Kristiansen U (2013) Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons. Neuropharmacology 66:99–113

  36. Kőszeghy Á, Vincze J, Rusznák Z, Fu Y, Paxinos G, Csernoch L, Szücs G (2012) Activation of muscarinic receptors increases the activity of the granule neurons of the rat dorsal cochlear nucleus—a calcium imaging study. Pflugers Arch 463(6):829–844

  37. Libri V, Constanti A, Zibetti M, Postlethwaite M (1997) Metabotropic glutamate receptor subtypes mediating slow inward tail current (IADP) induction and inhibition of synaptic transmission in olfactory cortical neurones. Br J Pharmacol 120(6):1083–1095

  38. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD, Hawrylycz MJ, Jones AR, Lein ES, Zeng H (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13(1):133–140

  39. Maloney K, Mainville L, Jones BE (1999) Differential c-Fos expression in cholinergic, monoaminergic, and GABAergic cell groups of the pontomesencephalic tegmentum after paradoxical sleep deprivation and recovery. J Neurosci 19(8):3057–3072

  40. Mannaioni G, Marino MJ, Valenti O, Traynelis SF, Conn PJ (2001) Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J Neurosci 21(16):5925–5934

  41. Mena-Segovia J, Sims HM, Magill PJ, Bolam JP (2008) Cholinergic brainstem neurons modulate cortical gamma activity during slow oscillations. J Physiol 586(12):2947–2960

  42. Min R, Nevian T (2012) Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nat Neurosci 15(5):746–753

  43. Moldrich G, Wenger T (2000) Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides 21(11):1735–1742

  44. Molina-Holgado F, Pinteaux E, Moore JD, Molina-Holgado E, Guaza C, Gibson RM, Rothwell NJ (2003) Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J Neurosci 23(16):6470–6474

  45. Murillo-Rodriguez E (2008) The role of the CB1 receptor in the regulation of sleep. Prog Neuropsychopharmacol Biol Psychiatry 32:1420–1427

  46. Murillo-Rodriguez E, Millán-Aldaco D, Di Marzo V, Drucker-Colín R (2008) The anandamide membrane transporter inhibitor VDM-11, modulates sleep and c-Fos expression in the rat brain. Neuroscience 157:1–11

  47. Murillo-Rodríguez E, Sánchez-Alavez M, Navarro L, Martínez-González D, Drucker-Colín R, Prospéro-García O (1998) Anandamide modulates sleep and memory in rats. Brain Res 812(1–2):270–274

  48. Murillo-Rodríguez E, Cabeza R, Méndez-Díaz M, Navarro L, Prospéro-García O (2001) Anandamide-induced sleep is blocked by SR141716A, a CB1 receptor antagonist and by U73122, a phospholipase C inhibitor. NeuroReport 12(10):2131–2136

  49. Navarrete M, Araque A (2008) Endocannabinoids mediate neuron-astrocyte communication. Neuron 58:883–893

  50. Navarrete M, Araque A (2010) Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron 68:113–126

  51. Navarrete M, Perea G, Fernandez de Sevilla D, Gómez-Gonzalo M, Núnez A, Martín ED, Araque A (2012) Astrocytes mediate in vivo cholinergic-induced synaptic plasticity. PLoS Biol 10(2):e1001259

  52. Nett WJ, Oloff SH, McCarthy KD (2002) Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity. J Neurophysiol 87(1):528–537

  53. Nimmerjahn A, Kirchhoff F, Kerr JN, Helmchen F (2004) Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo. Nat Methods 1:31–37

  54. Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322

  55. Pace-Schott EF (2009) Sleep architecture. In: Stickgold R, Walker M (eds) The neuroscience of sleep. Elsevier, Amsterdam, pp 10–17

  56. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369(6483):744–747

  57. Parri HR, Gould TM, Crunelli V (2010) Sensory and cortical activation of distinct glial cell subtypes in the somatosensory thalamus of young rats. Eur J Neurosci 32(1):29–40

  58. Partridge JG, Lewin AE, Yasko JR, Vicini S (2014) Contrasting actions of Group I metabotropic glutamate receptors in distinct mouse striatal neurones. J Physiol

  59. Pasantes Morales H, Schousboe A (1988) Volume regulation in astrocytes: a role for taurine as an osmoeffector. J Neurosci Res 20(4):503–509

  60. Paxinos G, Franklin KBJ (2004) The mouse brain atlas in stereotaxic coordinates. Elsevier, USA

  61. Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32(8):421–431

  62. Petralia RS, Wang YX, Niedzielski AS, Wenthold RJ (1996) The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71(4):949–976

  63. Pirttimaki TM, Parri HR (2012) Glutamatergic input–output properties of thalamic astrocytes. Neuroscience 205:18–28

  64. Pirttimaki TM, Hall SD, Parri HR (2011) Sustained neuronal activity generated by glial plasticity. J Neurosci 31(21):7637–7647

  65. Poisik OV, Mannaioni G, Traynelis S, Smith Y, Conn PJ (2003) Distinct functional roles of the metabotropic glutamate receptors 1 and 5 in the rat globus pallidus. J Neurosci 23(1):122–130

  66. Rainnie DG, Holmes KH, Shinnick-Gallagher P (1994) Activation of postsynaptic metabotropic glutamate receptors by trans-ACPD hyperpolarizes neurons of the basolateral amygdala. J Neurosci 14:7208–7220

  67. Reese NB, Garcia-Rill E, Skinner RD (1995) The pedunculopontine nucleus—auditory input, arousal and pathophysiology. Prog Neurobiol 42:105–133

  68. Rodriguez JJ, Mackie K, Pickel VM (2001) Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci 21(3):823–833

  69. Rodriguez-Cueto C, Benito C, Fernández-Ruiz J, Romero J, Hernández-Gálvez M, Gómez-Ruiz M (2013) Changes in Cb1 and Cb2 receptors in the postmortem cerebellum of humans affected by spinocerebellar ataxias. Br J Pharmacol. doi:10.1111/bph.12283

  70. Ros H, Magill PJ, Moss J, Bolam JP, Mena-Segovia J (2010) Distinct types of non-cholinergic pedunculopontine neurons are differentially modulated during global brain states. Neuroscience 170:78–91

  71. Rosenberg PA, Knowles R, Knowles KP, Li Y (1994) Beta-adrenergic receptor-mediated regulation of extracellular adenosine in cerebral cortex in culture. J Neurosci 14(5 Pt 2):2953–2965

  72. Salio C, Doly S, Fischer J, Franzoni MF, Conrath M (2002) Neuronal and astrocytic localization of the cannabinoid receptor-1 in the dorsal horn of the rat spinal cord. Neurosci Lett 329(1):13–16

  73. Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299(1):12–20

  74. Schools GP, Kimelberg HK (1999) mGluR3 and mGluR5 are the predominant metabotropic glutamate receptor mRNAs expressed in hippocampal astrocytes acutely isolated from young rats. J Neurosci Res 58(4):533–543

  75. Sherman SM (2014) The function of metabotropic glutamate receptors in thalamus and cortex. Neuroscientist 20(2):136–149

  76. Shibasaki K, Ikenaka K, Tamalu F, Tominaga M, Ishizaki Y (2014) A novel subtype of astrocytes expressing TRPV4 regulates neuronal excitability via release of gliotransmitters. J Biol Chem

  77. Smith RS, Weitz CJ, Araneda RC (2009) Excitatory actions of noradrenaline and metabotropic glutamate receptor activation in granule cells of the accessory olfactory bulb. J Neurophysiol 102(2):1103–1114

  78. Stella N (2004) Cannabinoid signaling in glial cells. Glia 48(4):267–277

  79. Ster J, Mateos JM, Grewe BF, Coiret G, Corti C, Corsi M, Helmchen F, Gerber U (2011) Enhancement of CA3 hippocampal network activity by activation of group II metabotropic glutamate receptors. Proc Natl Acad Sci USA 108(24):9993–9997

  80. Steriade M, Datta S, Paré D, Oakson G, Curró Dossi RC (1990) Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems. J Neurosci 10(8):2541–2559

  81. Szatkowski M, Barbour B, Attwell D (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 348(6300):443–446

  82. Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsiani D, Fu Y, Lu J, Lin Y, Miyoshi G, Shima Y, Fishell G, Nelson SB, Huang ZJ (2011) A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71(6):995–1013

  83. Tarokh L, Carskadon MA (2009) Sleep in adolescents. In: Stickgold R, Walker M (eds) The neuroscience of sleep. Elsevier, Amsterdam, pp 70–77

  84. Volterra A, Bezzi P (2002) Release of transmitters from glial cells, chap 13. In: Volterra A et al (eds) The tripartite synapse: glia in synaptic neurotransmission. Oxford University Press, Oxford, pp 164–184

  85. Walter L, Stella N (2003) Endothelin-1 increases 2-arachidonoyl glycerol (2-AG) production in astrocytes. Glia 44(1):85–90

  86. Warr O, Takahashi M, Attwell D (1999) Modulation of extracellular glutamate concentration in rat brain slices by cystine–glutamate exchange. J Physiol 514(Pt 3):783–793

  87. Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signaling at hippocampal synapses. Nature 410:588–592

  88. Wilson-Poe AR, Mitchell VA, Vaughan CW (2013) Postsynaptic mGluR mediated excitation of neurons in midbrain periaqueductal grey. Neuropharmacology 66:348–354

  89. Winn P (2006) How best to consider the structure and function of the pedunculopontine tegmental nucleus: evidence from animal studies. J Neurol Sci 248:234–250

  90. Xi ZX, Baker DA, Shen H, Carson DS, Kalivas PW (2002) Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens. J Pharmacol Exp Ther 300(1):162–171

  91. Ye ZC, Wyeth MS, Baltan-Tekkok S, Ransom BR (2003) Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23(9):3588–3596

  92. Zhang Z, Séguéla P (2010) Metabotropic induction of persistent activity in layers II/III of anterior cingulate cortex. Cereb Cortex 20(12):2948–2957

  93. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA 96(10):5780–5785

  94. Zur Nieden R, Deitmer JW (2006) The role of metabotropic glutamate receptors for the generation of calcium oscillations in rat hippocampal astrocytes in situ. Cereb Cortex 16(5):676–687

Download references

Acknowledgments

This work was supported by TÁMOP-4.2.2/B-10/1-2010-0024 and TÁMOP-4.2.2/A-11/1-KONV-2012-0025, the LP 003/2011 (TB), the Hungarian Academy of Sciences (grant number: MTA-TKI 242; AM) the János Bolyai Research Scholarship of the Hungarian Academy of Sciences, the Hungarian National Brain Research Program (KTIA_13_NAP-A-I/10. to BP and KTIA_13_NAP-A-I/8. to AM; KTIA_NAP_13-2-2014-0005 to PS), the research support grant of the Gedeon Richter Centenary Foundation, and the ‘Ányos Jedlik Scholarship’ of the ‘National Excellence Program’ of Hungary and the European Union TÁMOP 4.2.4. A/2-11-1-2012-0001 (ÁK). The authors are indebted to Professor Andreas Zimmer for providing us the CB1 knockout mouse strain, and to Professor Géza Szücs, Professor László Csernoch, Dr. Zoltán Rusznák, Dr. Attila Oláh and Dr. Attila Szöllősi for their help and valuable suggestions, and to Mrs. A. Varga for her technical support.

Conflict of interest

The authors declare no competing financial interests.

Author information

Correspondence to Balázs Pál.

Additional information

Á. Kőszeghy and A. Kovács contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 220 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kőszeghy, Á., Kovács, A., Bíró, T. et al. Endocannabinoid signaling modulates neurons of the pedunculopontine nucleus (PPN) via astrocytes. Brain Struct Funct 220, 3023–3041 (2015). https://doi.org/10.1007/s00429-014-0842-5

Download citation

Keywords

  • Pedunculopontine nucleus
  • CB1 receptor
  • Neuromodulation
  • Astrocyte
  • Metabotropic glutamate receptor