Abstract

Neuronal stimulation causes ∼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+/HCO3 − (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. Author Summary A key experimental observation associated with the astroglia–neuron interaction is the shrinkage of the extracellular space (ECS) that occurs in response to enhanced neuronal activation. Although well documented to be present in mammalian brains, this phenomenon has resisted a proper explanation since it was first reported. We present here a mathematical conceptualization that may explain the main mechanisms behind ECS shrinkage and provide a framework for a theoretical-experimental research programme that may help to reach a consensus explanation. Effective clearance of K+ is essential for normal brain function because an inappropriate increase in extracellular K+ will enhance neuronal excitability and promote neuronal afterdischarges and increase the probability of epileptic episodes. The shrinkage of the ECS usually appears in conjunction with K+ clearance and must be taken into account in a model of how astrocytes clear excess K+ following trains of action potentials. The present model allows us to make several clear and testable predictions addressing the relationship among potassium clearance, water transport, and ECS shrinkage. Among these are predictions concerning water transport functions of aquaporins in astrocytes, involvement of cotransporters in potassium clearance, and effects of particular knockouts on ECS shrinkage and ion concentrations.