title: Astrocytic mechanisms explaining neural-activity-induced shrinkage of extraneuronal space.
abstract: 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.
authors.affiliation: Centre for Integrative Genetics, Norwegian University of Life Sciences, As, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Østby
authors.forename: Leiv
authors.initials: L
authors.lastname: Øyehaug
authors.forename: Gaute T
authors.initials: GT
authors.lastname: Einevoll
authors.forename: Erlend A
authors.initials: EA
authors.lastname: Nagelhus
authors.forename: Erik
authors.initials: E
authors.lastname: Plahte
authors.forename: Thomas
authors.initials: T
authors.lastname: Zeuthen
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Lloyd
authors.forename: Ole P
authors.initials: OP
authors.lastname: Ottersen
authors.forename: Stig W
authors.initials: SW
authors.lastname: Omholt
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D009995:Osmosis / Q000502:physiology; D019899:Paracrine Communication / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D049490:Systems Biology
chemical_list: D001639:Bicarbonates; D002712:Chlorides; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium