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


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.

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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.

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The authors declare no competing financial interests.

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Correspondence to Balázs Pál.

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

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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

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