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The role of astrocytic calcium and TRPV4 channels in neurovascular coupling

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Abstract

Neuronal activity evokes a localised change in cerebral blood flow in a response known as neurovascular coupling (NVC). Although NVC has been widely studied the exact mechanisms that mediate this response remain unclear; in particular the role of astrocytic calcium is controversial. Mathematical modelling can be a useful tool for investigating the contribution of various signalling pathways towards NVC and for analysing the underlying cellular mechanisms. The lumped parameter model of a neurovascular unit with both potassium and nitric oxide (NO) signalling pathways and comprised of neurons, astrocytes, and vascular cells has been extended to include the glutamate induced astrocytic calcium pathway with epoxyeicosatrienoic acid (EET) signalling and the stretch dependent TRPV4 calcium channel on the astrocytic endfoot. Results show that the potassium pathway governs the fast onset of vasodilation while the NO pathway has a delayed response, maintaining dilation longer following neuronal stimulation. Increases in astrocytic calcium concentration via the calcium signalling pathway and/or TRPV4 channel to levels consistent with experimental data are insufficient for inducing either vasodilation or constriction, in contrast to a number of experimental results. It is shown that the astrocyte must depolarise in order to produce a significant potassium flux through the astrocytic BK channel. However astrocytic calcium is shown to strengthen potassium induced NVC by opening the BK channel further, consequently allowing more potassium into the perivascular space. The overall effect is vasodilation with a higher maximal vessel radius.

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Abbreviations

C a 2+ :

calcium.

I P 3 :

inotisol trisphosphate.

K + :

potassium.

20-HETE:

20- hydroxyeicosatetraenoic acid.

AA:

arachidonic acid.

ATP:

adenosine triphosphate.

BK:

big potassium.

cGMP:

cyclic guanosine monophosphate.

COX:

cyclooxegenase enzymes.

CPI-17:

myosin phosphatase inhibitor protein.

CSD:

cortical spreading depression.

EC:

endothelial cell.

ECS:

extracellular space.

EET:

epoxyeicosatrienoic acid.

EFS:

electro field stimulation.

ER:

endoplasmic reticulum.

KIR:

inward rectifying potassium (K +).

mGluR:

metabotropic glutamate receptor.

MLC:

myosin light chain kinase.

NMDA:

N-methyl-D-aspartate.

NO:

nitric oxide.

NVC:

neurovascular coupling.

NVU:

neurovascular unit.

ODE:

ordinary differential equation.

PgE2 :

prostaglandin E2.

PKC:

protein-kinase C.

PVS:

perivascular space.

SC:

synaptic cleft.

sGC:

soluble guanylyl cyclase.

SMC:

smooth muscle cell.

TRPV4:

transient receptor potential vanniloid-related 4.

VOCC:

voltage operated calcium (C a 2+) channel.

WSS:

wall shear stress.

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Acknowledgements

The authors wish to thank the University of Canterbury and Brain Research New Zealand for providing PhD funding for this project.

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Correspondence to Allanah Kenny.

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Action Editor: Upinder Singh Bhalla

Appendix: Model parameters

Appendix: Model parameters

All parameters used for the model components discussed in Sections 2 and 3 are given in Tables 14. See Dormanns et al. (2015) and Dormanns et al. (2016) for the remaining parameters.

Table 1 Model parameters related to the neuronal input functions K(t) and Glu (t)
Table 2 Model parameters related to the astrocytic calcium (C a 2+) pathway
Table 3 Model parameters related to the TRPV4 channel
Table 4 Model parameters related to the ECS compartment

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Kenny, A., Plank, M.J. & David, T. The role of astrocytic calcium and TRPV4 channels in neurovascular coupling. J Comput Neurosci 44, 97–114 (2018). https://doi.org/10.1007/s10827-017-0671-7

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  • DOI: https://doi.org/10.1007/s10827-017-0671-7

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