A Critical Role for Purinergic Signalling in the Mechanisms Underlying Generation of BOLD fMRI Responses
- Jack A. Wells1,*,
- Isabel N. Christie1,2,*,
- Patrick S. Hosford2,
- Robert T.R. Huckstepp2,
- Plamena R. Angelova3,
- Pirkko Vihko4,
- Simon C. Cork2,
- Andrey Y. Abramov3,
- Anja G. Teschemacher5,
- Sergey Kasparov5,†,
- Mark F. Lythgoe1,†, and
- Alexander V. Gourine2,†
- 1University College London Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, WC1E 6DD, United Kingdom,
- 2Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, United Kingdom,
- 3Institute of Neurology, University College London, London, WC1N 3BG, United Kingdom,
- 4Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital Laboratory, 00100 Helsinki, Finland, and
- 5School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom
-
Author contributions: I.N.C., A.Y.A., S.K., M.F.L., and A.V.G. designed research; J.A.W., I.N.C., P.S.H., R.T.R.H., P.R.A., S.C.C., and A.G.T. performed research; P.V. contributed unpublished reagents/analytic tools; J.A.W., I.N.C., R.T.R.H., A.Y.A., S.K., and A.V.G. analyzed data; I.N.C., S.K., and A.V.G. wrote the paper.
-
↵*J.A.W. and I.N.C. contributed equally to this study as joint first authors.
-
↵†S.K., M.F.L., and A.V.G. contributed equally to this study as joint last authors.
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.
- Received September 10, 2014.
- Revision received February 5, 2015.
- Accepted February 24, 2015.
- Copyright © 2015 the authors 0270-6474/15/355284-09$15.00/0
This article is freely available online through the J Neurosci Author Open Choice option.
