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Comment
. 2021 Apr 17;6(1):160.
doi: 10.1038/s41392-021-00586-4.

Surveilling microglia dampens neuronal activity: operation of a purinergically mediated negative feedback mechanism

Peter Illes  1   2   3 , Alexei Verkhratsky  4   5 , Yong Tang  6   4
Affiliations
Comment

Surveilling microglia dampens neuronal activity: operation of a purinergically mediated negative feedback mechanism

Peter Illes et al. Signal Transduct Target Ther. .
No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Microglia–neuron cross-talk at different microglial activation states. a Surveilling/ramified microglia send their processes to the ATP-releasing terminals of neurons as well as to their somata where the plasma membrane covers ATP-producing mitochondria. Neuronally released ATP is gradually degraded by CD39 to ADP and AMP, and then by CD73 to adenosine (ADO). Adenosine is inactivated by adenosine deaminase (ADOD) to inosine (INO). P2Y12Rs respond to transmitter ATP or somatically released ATP by increased coverage by microglial processes of these neuronal sites. A3Rs and P2Y12Rs act in concert to promote microglial process motility. Adenosine feeds back via presynaptic or somatic A1Rs to inhibit neuronal activity. b Activated/ameboid microglia phagocytose bacteria or cellular debris. ATP may be again released as a neurotransmitter but may also leave the neuronal cytoplasm via holes in the damaged cellular membrane. In addition, ATP is outpouring from neighboring astrocytes mainly through connexin channels and pannexin-1 hemichannels in a nonexocytotic manner. Instead of P2Y12Rs, now P2X7Rs are the main microglial sites at which ATP acts. P2X7Rs are pathways for the release of ATP, and more importantly, they induce the production/release of proinflammatory cytokines (IL-1β, TNF-α) and reactive oxygen species (ROS). These cell products cause neuroinflammation and subsequent neuronal damage through the activation of their specific receptors (IL-1R, TNFαR). P2X7Rs act in synchrony with P2X4Rs. A2ARs promote the transition of ramified microglia to ameboid microglia. UDP-sensitive P2Y6Rs trigger microglial phagocytosis, while UTP (ATP)-sensitive P2Y4Rs trigger microglial pinocytosis. UTP/UDP derives from the nucleus of injured cellular material. Whereas A1Rs at neurons are inhibitory, A2ARs are excitatory and they promote neurodegeneration
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Comment on

  • Negative feedback control of neuronal activity by microglia.
    Badimon A, Strasburger HJ, Ayata P, Chen X, Nair A, Ikegami A, Hwang P, Chan AT, Graves SM, Uweru JO, Ledderose C, Kutlu MG, Wheeler MA, Kahan A, Ishikawa M, Wang YC, Loh YE, Jiang JX, Surmeier DJ, Robson SC, Junger WG, Sebra R, Calipari ES, Kenny PJ, Eyo UB, Colonna M, Quintana FJ, Wake H, Gradinaru V, Schaefer A. Badimon A, et al. Nature. 2020 Oct;586(7829):417-423. doi: 10.1038/s41586-020-2777-8. Epub 2020 Sep 30. Nature. 2020. PMID: 32999463 Free PMC article.

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