Astrocytic mechanisms explaining neural-activity-induced shrinkage of extraneuronal space

TY - JOUR

T1 - Astrocytic mechanisms explaining neural-activity-induced shrinkage of extraneuronal space

AU - Østby, Ivar

AU - Øyehaug, Leiv

AU - Einevoll, Gaute T

AU - Nagelhus, Erlend A

AU - Plahte, Erik

AU - Zeuthen, Thomas

AU - Lloyd, Catherine M

AU - Ottersen, Ole P

AU - Omholt, Stig W

N1 - Keywords: Animals; Astrocytes; Bicarbonates; Chlorides; Extracellular Space; Humans; Ion Transport; Membrane Potentials; Models, Biological; Neurons; Osmosis; Paracrine Communication; Potassium; Sodium; Sodium-Potassium-Exchanging ATPase; Systems Biology

PY - 2009

Y1 - 2009

N2 - Neuronal stimulation causes approximately 30% shrinkage of the extracellular space (ECS) between neurons and surrounding astrocytes in grey and white matter under experimental conditions. Despite its possible implications for a proper understanding of basic aspects of potassium clearance and astrocyte function, the phenomenon remains unexplained. Here we present a dynamic model that accounts for current experimental data related to the shrinkage phenomenon in wild-type as well as in gene knockout individuals. We find that neuronal release of potassium and uptake of sodium during stimulation, astrocyte uptake of potassium, sodium, and chloride in passive channels, action of the Na/K/ATPase pump, and osmotically driven transport of water through the astrocyte membrane together seem sufficient for generating ECS shrinkage as such. However, when taking into account ECS and astrocyte ion concentrations observed in connection with neuronal stimulation, the actions of the Na(+)/K(+)/Cl(-) (NKCC1) and the Na(+)/HCO(3) (-) (NBC) cotransporters appear to be critical determinants for achieving observed quantitative levels of ECS shrinkage. Considering the current state of knowledge, the model framework appears sufficiently detailed and constrained to guide future key experiments and pave the way for more comprehensive astroglia-neuron interaction models for normal as well as pathophysiological situations.

AB - Neuronal stimulation causes approximately 30% shrinkage of the extracellular space (ECS) between neurons and surrounding astrocytes in grey and white matter under experimental conditions. Despite its possible implications for a proper understanding of basic aspects of potassium clearance and astrocyte function, the phenomenon remains unexplained. Here we present a dynamic model that accounts for current experimental data related to the shrinkage phenomenon in wild-type as well as in gene knockout individuals. We find that neuronal release of potassium and uptake of sodium during stimulation, astrocyte uptake of potassium, sodium, and chloride in passive channels, action of the Na/K/ATPase pump, and osmotically driven transport of water through the astrocyte membrane together seem sufficient for generating ECS shrinkage as such. However, when taking into account ECS and astrocyte ion concentrations observed in connection with neuronal stimulation, the actions of the Na(+)/K(+)/Cl(-) (NKCC1) and the Na(+)/HCO(3) (-) (NBC) cotransporters appear to be critical determinants for achieving observed quantitative levels of ECS shrinkage. Considering the current state of knowledge, the model framework appears sufficiently detailed and constrained to guide future key experiments and pave the way for more comprehensive astroglia-neuron interaction models for normal as well as pathophysiological situations.

U2 - 10.1371/journal.pcbi.1000272

DO - 10.1371/journal.pcbi.1000272

M3 - Journal article

C2 - 19165313

SN - 1553-734X

VL - 5

SP - e1000272

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 1

ER -