Ca2+-dependent release of ATP from astrocytes affects herpes simplex virus type 1 infection of neurons

Domenica Donatella Li Puma, Maria Elena Marcocci, Giacomo Lazzarino, Giovanna De Chiara, Barbara Tavazzi, Anna Teresa Palamara, Roberto Piacentini, Claudio Grassi

Research output: Contribution to journalArticlepeer-review


Astrocytes provide metabolic support for neurons and modulate their functions by releasing a plethora of neuroactive molecules diffusing to neighboring cells. Here we report that astrocytes also play a role in cortical neurons' vulnerability to Herpes simplex virus type-1 (HSV-1) infection through the release of extracellular ATP. We found that the interaction of HSV-1 with heparan sulfate proteoglycans expressed on the plasma membrane of astrocytes triggered phospholipase C-mediated IP3-dependent intracellular Ca2+ transients causing extracellular release of ATP. ATP binds membrane purinergic P2 receptors (P2Rs) of both neurons and astrocytes causing an increase in intracellular Ca2+ concentration that activates the Glycogen Synthase Kinase (GSK)-3β, whose action is necessary for HSV-1 entry/replication in these cells. Indeed, in co-cultures of neurons and astrocytes HSV-1-infected neurons were only found in proximity of infected astrocytes releasing ATP, whereas in the presence of fluorocitrate, an inhibitor of astrocyte metabolism, switching-off the HSV-1-induced ATP release, very few neurons were infected. The addition of exogenous ATP, mimicking that released by astrocytes after HSV-1 challenge, restored the ability of HSV-1 to infect neurons co-cultured with metabolically-inhibited astrocytes. The ATP-activated, P2R-mediated, and GSK-3-dependent molecular pathway underlying HSV-1 infection is likely shared by neurons and astrocytes, given that the blockade of either P2Rs or GSK-3 activation inhibited infection of both cell types. These results add a new layer of information to our understanding of the critical role played by astrocytes in regulating neuronal functions and their response to noxious stimuli including microbial agents via Ca2+-dependent release of neuroactive molecules.

Original languageEnglish
Pages (from-to)201-215
Number of pages15
Issue number1
Publication statusPublished - Jan 2021


  • astrocytes
  • ATP
  • GSK-3β
  • herpes simplex virus
  • P2Rs

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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