title: A critical role for purinergic signalling in the mechanisms underlying generation of BOLD fMRI responses.
abstract: The mechanisms of neurovascular coupling underlying generation of BOLD fMRI signals remain incompletely understood. It has been proposed that release of vasoactive substances by astrocytes couples neuronal activity to changes in cerebrovascular blood flow. However, the role of astrocytes in fMRI responses remains controversial. Astrocytes communicate via release of ATP, and here we tested the hypothesis that purinergic signaling plays a role in the mechanisms underlying fMRI. An established fMRI paradigm was used to trigger BOLD responses in the forepaw region of the somatosensory cortex (SSFP) of an anesthetized rat. Forepaw stimulation induced release of ATP in the SSFP region. To interfere with purinergic signaling by promoting rapid breakdown of the vesicular and/or released ATP, a lentiviral vector was used to express a potent ectonucleotidase, transmembrane prostatic acid phosphatase (TMPAP), in the SSFP region. TMPAP expression had no effect on resting cerebral blood flow, cerebrovascular reactivity, and neuronal responses to sensory stimulation. However, TMPAP catalytic activity markedly reduced the magnitude of BOLD fMRI responses triggered in the SSFP region by forepaw stimulation. Facilitated ATP breakdown could result in accumulation of adenosine. However, blockade of A1 receptors had no effect on BOLD responses and did not reverse the effect of TMPAP. These results suggest that purinergic signaling plays a significant role in generation of BOLD fMRI signals. We hypothesize that astrocytes activated during periods of enhanced neuronal activity release ATP, which propagates astrocytic activation, stimulates release of vasoactive substances and dilation of cerebral vasculature.
authors.affiliation: University College London Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, WC1E 6DD, United Kingdom.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Wells
authors.affiliation: University College London Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, WC1E 6DD, United Kingdom, Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Isabel N
authors.initials: IN
authors.lastname: Christie
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Hosford
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Robert T R
authors.initials: RT
authors.lastname: Huckstepp
authors.affiliation: Institute of Neurology, University College London, London, WC1N 3BG, United Kingdom.
authors.forename: Plamena R
authors.initials: PR
authors.lastname: Angelova
authors.affiliation: Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital Laboratory, 00100 Helsinki, Finland, and.
authors.forename: Pirkko
authors.initials: P
authors.lastname: Vihko
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Cork
authors.affiliation: Institute of Neurology, University College London, London, WC1N 3BG, United Kingdom.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Anja G
authors.identifier: http://orcid.org/0000-0002-5514-2669
authors.initials: AG
authors.lastname: Teschemacher
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom sergey.kasparov@bristol.ac.uk a.gourine@ucl.ac.uk.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kasparov
authors.affiliation: University College London Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, WC1E 6DD, United Kingdom.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom, sergey.kasparov@bristol.ac.uk a.gourine@ucl.ac.uk.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
mesh_terms: D000135:Acid Phosphatase; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D005552:Forelimb / Q000502:physiology; D059907:Functional Neuroimaging; D008279:Magnetic Resonance Imaging; D008297:Male; D008845:Microinjections; D017027:Protein Tyrosine Phosphatases / Q000008:administration & dosage / Q000235:genetics; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013003:Somatosensory Cortex / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D000255:Adenosine Triphosphate; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases
keywords: ATP; BOLD; astrocyte; fMRI; glia; neurovascular coupling
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