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Brain Structure and Function

, Volume 222, Issue 1, pp 247–266 | Cite as

Direct presynaptic and indirect astrocyte-mediated mechanisms both contribute to endocannabinoid signaling in the pedunculopontine nucleus of mice

  • A. Kovács
  • Cs. Bordás
  • T. Bíró
  • Z. Hegyi
  • M. Antal
  • P. Szücs
  • Balázs PálEmail author
Original Article

Abstract

The pedunculopontine nucleus (PPN), a cholinergic nucleus of the reticular activating system, is known to be involved in the regulation of sleep and wakefulness. Endogenous and exogenous cannabinoids, by systemic or local administration to the pedunculopontine nucleus, can both influence sleep. We previously demonstrated that activation of astrocytes by cannabinoid type 1 (CB1) receptor agonists was able to modulate the membrane potential of PPN neurons, even in the presence of blockers of fast synaptic neurotransmission. In the present work, we provide evidence that synaptic inputs of PPN neurons are also affected by activation of presynaptic and astrocytic CB1 receptors. Using slice electrophysiology combined with calcium imaging, optogenetics and immunohistochemistry, we revealed a direct presynaptic inhibitory action on inhibitory postsynaptic currents, along with a mild increase of excitatory postsynaptic currents during CB1 receptor stimulation. Besides inhibition of excitatory and inhibitory neurotransmission through stimulation of presynaptic CB1 receptors, astrocyte- and mGluR-dependent tonic inhibition and excitation also developed. The mild stimulatory action of CB1 receptor activation on excitatory neurotransmission is the combination of astrocyte-dependent tonic excitation on excitatory neurons and the canonical presynaptic CB1 receptor activation and consequential inhibition of excitatory synaptic neurotransmission, whereas the astrocyte-dependent stimulatory action was not observed in inhibitory neurotransmission within the PPN. Our findings demonstrate that endocannabinoids act in the PPN via a dual pathway, consisting of a direct presynaptic and an indirect, astrocyte-mediated component, regulating synaptic strength and neuronal activity via independent mechanisms.

Keywords

Pedunculopontine nucleus CB1 receptor Optogenetics Astrocyte Neuromodulation 

Notes

Acknowledgments

This work was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences, the Szodoray Fellowship of the University of Debrecen, the Hungarian National Brain Research Program (KTIA_13_NAP-A-I/10 to BP; KTIA_NAP_13-1-2013-0001 to MA; KTIA_NAP_13-2-2014-0005 to PS) and the Hungarian Academy of Sciences (MTA-TKI 242; MA), and TÁMOP-4.2.2.B-15/1/KONV-2015-0001 (AK, CB). The authors are indebted to Professor Andreas Zimmer for providing us the CB1 knockout mouse strain and to Professor László Csernoch and Dr. Péter Szentesi for providing Rhod-2 fluorescent dye and for the valuable discussion of the results of this project.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interest.

Supplementary material

429_2016_1214_MOESM1_ESM.docx (139 kb)
Supplementary material 1 (DOCX 139 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • A. Kovács
    • 1
  • Cs. Bordás
    • 1
  • T. Bíró
    • 1
    • 2
  • Z. Hegyi
    • 3
  • M. Antal
    • 3
    • 4
  • P. Szücs
    • 1
    • 5
  • Balázs Pál
    • 1
    Email author
  1. 1.Department of Physiology, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  2. 2.Department of Immunology, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  3. 3.Department of Anatomy, Histology and Embryology, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  4. 4.MTA-DE Neuroscience Research GroupDebrecenHungary
  5. 5.MTA-DE-NAP B-Pain Control Research GroupDebrecenHungary

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