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Event Details

  • Tuesday, April 10, 2018
  • 18:30 - 18:40

Roman Serrat - Modulation of Astroglial Calcium Signaling by Mitochondrial Type 1 Cannabinoid Receptor

Mitochondrial Ca2+ plays a critical physiological role in cellular energy metabolism and signalling, and its overload contributes to various pathological conditions including neuronal apoptotic death in neurological diseases. It is known that the type-1 cannabinoid receptor (CB1) is present at the mitochondria (mtCB1) and the activation of these receptors decreases cellular respiration and dysregulates memory processes. Data from our lab now show that the CB1 receptor is also present in the mitochondria of astrocytes and can regulate energy production in this cell context. However, it is still not clear whether mtCB1 participates in the synaptic effect of CB1 in astrocytes and if this is mediated by the reported decrease in ATP production or by a regulation in the Ca2+ buffering capacity of mitochondria. Using confocal microscopy in isolated astrocytes transfected with a genetically encoded Ca2+ indicator (GCAMP6s) targeted to mitochondria and a cytosolic Ca2+ sensor (RCAMP2), we have shown that CB1 activation by the specific agonist WIN 55,212-2 leads to an increase of Ca2+ in both compartments. Conversely, a mutant CB1 that it is not addressed to mitochondria (DN22-CB1) only affects cytosolic Ca2+. These results demonstrate that mtCB1 receptor regulates Ca2+ levels in the mitochondria. The inhibitor of soluble adenylyl cyclase (sAC) KH7, that blocks mtCB1-dependent respiration, does not affect cannabinoid-induced increase of mitochondrial Ca2+ in astrocytes, suggesting that this effect of mtCB1 might be independent from cellular respiration. Moreover, the inhibitors of the IP3 receptor located in the endoplasmic reticulum (ER) 2-APB and Xestospongin C blocked the WIN-dependent mitochondrial Ca2+ increase, suggesting that the ER is the source responsible for the increase of Ca2+ in the mitochondria. To investigate if these “in vitro” experiments are reproducible in an “in vivo” model, the somatosensory cortex of WT mice was infected with AAV viruses expressing the mitochondrial GCAMP6s sensor under the astroglial promoter GFAP and the activity of mitochondrial Ca2+ monitored using a 2-photon microscopy in anesthetized animals. Preliminary results show that the intraperitoneal injection of the CB1 agonist THC increases the % of activated mitochondria particles. To conclude, this work shows that mtCB1 regulates Ca2+ levels in the mitochondria of astrocytes, representing a potential novel mechanism by which astroglial CB1 receptors could control astroglial functions and synaptic plasticity.