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Fast Ca$^{2+}$ responses in astrocyte end-feet and neurovascular coupling in mice

Barbara Lykke Lind 1, * Sanne Barsballe Jessen 1 Micael Lønstrup 1 Charlène Joséphine 2 Gilles Bonvento 2 Martin Lauritzen 2, 3 
* Corresponding author
2 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
MIRCEN - Service MIRCEN : DRF/JACOB, CNRS - Centre National de la Recherche Scientifique : UMR 9199
Abstract : 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 Ca$^{2+}$ changes in astrocytes versus neurons. Here, we used two-photon microscopy to assess Ca$^{2+}$ 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 Ca$^{2+}$ signals in the subcellular compartments of astrocytes. Fast Ca$^{2+}$ responses were observed using both chemical and genetically encoded Ca$^{2+}$ 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 Ca$^{2+}$ 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 Ca$^{2+}$ response in astrocyte end-feet but did not affect Ca$^{2+}$ responses in astrocyte processes and neuropil. These results suggest that fast Ca$^{2+}$ increases in the neuropil and astrocyte processes are not necessary for an evoked CBF response. In contrast, as local fast Ca$^{2+}$ 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 Ca$^{2+}$ increases in end-feet adjust CBF during synaptic activity.
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Barbara Lykke Lind, Sanne Barsballe Jessen, Micael Lønstrup, Charlène Joséphine, Gilles Bonvento, et al.. Fast Ca$^{2+}$ responses in astrocyte end-feet and neurovascular coupling in mice. Glia, Wiley, 2018, 66 (2), pp.348-358. ⟨10.1002/glia.23246⟩. ⟨cea-02159356⟩



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