title: Pyramidal cells and cytochrome P450 epoxygenase products in the neurovascular coupling response to basal forebrain cholinergic input.
abstract: Activation of the basal forebrain (BF), the primary source of acetylcholine (ACh) in the cortex, broadly increases cortical cerebral blood flow (CBF), a response downstream to ACh release. Although endothelial nitric oxide and cholinoceptive GABA (γ-aminobutyric acid) interneurons have been implicated, little is known about the role of pyramidal cells in this response and their possible interaction with astrocytes. Using c-Fos immunohistochemistry as a marker of neuronal activation and laser-Doppler flowmetry, we measured changes in CBF evoked by BF stimulation following pharmacological blockade of c-Fos-identified excitatory pathways, astroglial metabolism, or vasoactive mediators. Pyramidal cells including those that express cyclooxygenase-2 (COX-2) displayed c-Fos upregulation. Glutamate acting via NMDA, AMPA, and mGlu receptors was involved in the evoked CBF response, NMDA receptors having the highest contribution (~33%). In contrast, nonselective and selective COX-2 inhibition did not affect the evoked CBF response (+0.4% to 6.9%, ns). The metabolic gliotoxins fluorocitrate and fluoroacetate, the cytochrome P450 epoxygenase inhibitor MS-PPOH and the selective epoxyeicosatrienoic acids (EETs) antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) all blocked the evoked CBF response by ~50%. Together, the data demonstrate that the hyperemic response to BF stimulation is largely mediated by glutamate released from activated pyramidal cells and by vasoactive EETs, likely originating from activated astrocytes.
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lecrux
authors.forename: Ara
authors.initials: A
authors.lastname: Kocharyan
authors.forename: Claire H
authors.initials: CH
authors.lastname: Sandoe
authors.forename: Xin-Kang
authors.initials: XK
authors.lastname: Tong
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000109:Acetylcholine / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D002951:Citrates / Q000633:toxicity; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology*; D005463:Fluoroacetates / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C494022:14,15-eicosa-5-enoic acid; D000577:Amides; D002951:Citrates; D005463:Fluoroacetates; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; C007744:fluorocitrate; D005680:gamma-Aminobutyric Acid; C014815:fluoroacetic acid; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015126:8,11,14-Eicosatrienoic Acid; D000109:Acetylcholine