Journal
GLIA
Volume 66, Issue 2, Pages 348-358Publisher
WILEY
DOI: 10.1002/glia.23246
Keywords
astrocyte end-feet; blood flow regulation; calcium imaging; in vivo; pixel detection
Categories
Funding
- Lundbeck Foundation
- NOVO-Nordisk Foundation
- Danish Medical Research Council
- NORDEA Foundation for the Center for Healthy Aging
- Fondation Leducq
- Lundbeck Foundation [R126-2012-12462, R210-2015-3320] Funding Source: researchfish
- Novo Nordisk Fonden [NNF15OC0017366] Funding Source: researchfish
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Cerebral blood flow (CBF) is regulated by the activity of neurons and astrocytes. Understanding how these cells control activity-dependent increases in CBF is crucial to interpreting functional neuroimaging signals. The relative importance of neurons and astrocytes is debated, as are the functional implications of fast Ca2+ changes in astrocytes versus neurons. Here, we used two-photon microscopy to assess Ca2+ changes in neuropil, astrocyte processes, and astrocyte end-feet in response to whisker pad stimulation in mice. We also developed a pixel-based analysis to improve the detection of rapid Ca2+ signals in the subcellular compartments of astrocytes. Fast Ca2+ responses were observed using both chemical and genetically encoded Ca2+ indicators in astrocyte end-feet prior to dilation of arterioles and capillaries. A low dose of the NMDA receptor antagonist (5R,10s)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-hydrogen-maleate (MK801) attenuated fast Ca2+ responses in the neuropil and astrocyte processes, but not in astrocyte end-feet, and the evoked CBF response was preserved. In addition, a low dose of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), an agonist for the extrasynaptic GABA(A) receptor (GABA(A)R), increased CBF responses and the fast Ca2+ response in astrocyte end-feet but did not affect Ca2+ responses in astrocyte processes and neuropil. These results suggest that fast Ca2+ increases in the neuropil and astrocyte processes are not necessary for an evoked CBF response. In contrast, as local fast Ca2+ responses in astrocyte end-feet are unaffected by MK801 but increase via GABA(A)R-dependent mechanisms that also increased CBF responses, we hypothesize that the fast Ca2+ increases in end-feet adjust CBF during synaptic activity.
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