title: COX-2-Derived Prostaglandin E2 Produced by Pyramidal Neurons Contributes to Neurovascular Coupling in the Rodent Cerebral Cortex.
abstract: Vasodilatory prostaglandins play a key role in neurovascular coupling (NVC), the tight link between neuronal activity and local cerebral blood flow, but their precise identity, cellular origin and the receptors involved remain unclear. Here we show in rats that NMDA-induced vasodilation and hemodynamic responses evoked by whisker stimulation involve cyclooxygenase-2 (COX-2) activity and activation of the prostaglandin E2 (PgE2) receptors EP2 and EP4. Using liquid chromatography-electrospray ionization-tandem mass spectrometry, we demonstrate that PgE2 is released by NMDA in cortical slices. The characterization of PgE2 producing cells by immunohistochemistry and single-cell reverse transcriptase-PCR revealed that pyramidal cells and not astrocytes are the main cell type equipped for PgE2 synthesis, one third expressing COX-2 systematically associated with a PgE2 synthase. Consistent with their central role in NVC, in vivo optogenetic stimulation of pyramidal cells evoked COX-2-dependent hyperemic responses in mice. These observations identify PgE2 as the main prostaglandin mediating sensory-evoked NVC, pyramidal cells as their principal source and vasodilatory EP2 and EP4 receptors as their targets.
  
  
  CONCLUSIONS
  Brain function critically depends on a permanent spatiotemporal match between neuronal activity and blood supply, known as NVC. In the cerebral cortex, prostaglandins are major contributors to NVC. However, their biochemical identity remains elusive and their cellular origins are still under debate. Although astrocytes can induce vasodilations through the release of prostaglandins, the recruitment of this pathway during sensory stimulation is questioned. Using multidisciplinary approaches from single-cell reverse transcriptase-PCR, mass spectrometry, to ex vivo and in vivo pharmacology and optogenetics, we provide compelling evidence identifying PgE2 as the main prostaglandin in NVC, pyramidal neurons as their main cellular source and the vasodilatory EP2 and EP4 receptors as their main targets. These original findings will certainly change the current view of NVC.
authors: Sorbonne Universités, UPMC Université Paris 06, Institut de Biologie Paris-Seine (IBPS), UM 119, Neuroscience Paris Seine, F-75005, Paris, France, CNRS, UMR 8246, Neuroscience Paris Seine, F-75005, Paris, France, INSERM, UMR-S 1130, Neuroscience Paris Seine, F-75005, Paris, France.
authors: Alexandre
authors: A
authors: Lacroix
authors: Sorbonne Universités, UPMC Université Paris 06, Institut de Biologie Paris-Seine (IBPS), UM 119, Neuroscience Paris Seine, F-75005, Paris, France, CNRS, UMR 8246, Neuroscience Paris Seine, F-75005, Paris, France, INSERM, UMR-S 1130, Neuroscience Paris Seine, F-75005, Paris, France, Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec H3A 2B4, Canada.
authors: Xavier
authors: X
authors: Toussay
authors: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors: Eitan
authors: E
authors: Anenberg
authors: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec H3A 2B4, Canada.
authors: Clotilde
authors: C
authors: Lecrux
authors: Department of Clinical Pharmacology, University-Hospital Frankfurt, 60590 Frankfurt am Main, Germany, and.
authors: Nerea
authors: N
authors: Ferreirós
authors: Sorbonne Universités, UPMC Université Paris 06, Institut de Biologie Paris-Seine (IBPS), UM 119, Neuroscience Paris Seine, F-75005, Paris, France, CNRS, UMR 8246, Neuroscience Paris Seine, F-75005, Paris, France, INSERM, UMR-S 1130, Neuroscience Paris Seine, F-75005, Paris, France.
authors: Anastassios
authors: A
authors: Karagiannis
authors: Sorbonne Universités, UPMC Université Paris 06, Institut de Biologie Paris-Seine (IBPS), UM 119, Neuroscience Paris Seine, F-75005, Paris, France, CNRS, UMR 8246, Neuroscience Paris Seine, F-75005, Paris, France, INSERM, UMR-S 1130, Neuroscience Paris Seine, F-75005, Paris, France.
authors: Fabrice
authors: F
authors: Plaisier
authors: Sorbonne Universités, UPMC Université Paris 06, Institut de Biologie Paris-Seine (IBPS), UM 119, Neuroscience Paris Seine, F-75005, Paris, France, CNRS, UMR 8246, Neuroscience Paris Seine, F-75005, Paris, France, INSERM, UMR-S 1130, Neuroscience Paris Seine, F-75005, Paris, France.
authors: Patrick
authors: P
authors: Chausson
authors: Sorbonne Universités, UPMC Université Paris 06, Institut de Biologie Paris-Seine (IBPS), UM 119, Neuroscience Paris Seine, F-75005, Paris, France, CNRS, UMR 8246, Neuroscience Paris Seine, F-75005, Paris, France, INSERM, UMR-S 1130, Neuroscience Paris Seine, F-75005, Paris, France.
authors: Frédéric
authors: F
authors: Jarlier
authors: Department of Biomedical Engineering, Columbia University, New York, New York 10027.
authors: Sean A
authors: SA
authors: Burgess
authors: Department of Biomedical Engineering, Columbia University, New York, New York 10027.
authors: Elizabeth M C
authors: EM
authors: Hillman
authors: Department of Clinical Pharmacology, University-Hospital Frankfurt, 60590 Frankfurt am Main, Germany, and.
authors: Irmgard
authors: I
authors: Tegeder
authors: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors: Timothy H
authors: TH
authors: Murphy
authors: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec H3A 2B4, Canada.
authors: Edith
authors: E
authors: Hamel
authors: Sorbonne Universités, UPMC Université Paris 06, Institut de Biologie Paris-Seine (IBPS), UM 119, Neuroscience Paris Seine, F-75005, Paris, France, CNRS, UMR 8246, Neuroscience Paris Seine, F-75005, Paris, France, INSERM, UMR-S 1130, Neuroscience Paris Seine, F-75005, Paris, France, bruno.cauli@upmc.fr.
authors: Bruno
authors: B
authors: Cauli
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014664:Vasodilation / Q000502:physiology*
chemical_list: C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: astrocytes; cerebral cortex; cyclooxygenase-2; interneurons; pyramidal cells