Aquaporin-4–dependent K+ and water transport modeled in brain extracellular space following neuroexcitation

Abstract

Potassium (K+) ions released into brain extracellular space (ECS) during neuroexcitation are efficiently taken up by astrocytes. Deletion of astrocyte water channel aquaporin-4 (AQP4) in mice alters neuroexcitation by reducing ECS [K+] accumulation and slowing K+ reuptake. These effects could involve AQP4-dependent: (a) K+ permeability, (b) resting ECS volume, (c) ECS contraction during K+ reuptake, and (d) diffusion-limited water/K+ transport coupling. To investigate the role of these mechanisms, we compared experimental data to predictions of a model of K+ and water uptake into astrocytes after neuronal release of K+ into the ECS. The model computed the kinetics of ECS [K+] and volume, with input parameters including initial ECS volume, astrocyte K+ conductance and water permeability, and diffusion in astrocyte cytoplasm. Numerical methods were developed to compute transport and diffusion for a nonstationary astrocyte–ECS interface. The modeling showed that mechanisms b–d, together, can predict experimentally observed impairment in K+ reuptake from the ECS in AQP4 deficiency, as well as altered K+ accumulation in the ECS after neuroexcitation, provided that astrocyte water permeability is sufficiently reduced in AQP4 deficiency and that solute diffusion in astrocyte cytoplasm is sufficiently low. The modeling thus provides a potential explanation for AQP4-dependent K+/water coupling in the ECS without requiring AQP4-dependent astrocyte K+ permeability. Our model links the physical and ion/water transport properties of brain cells with the dynamics of neuroexcitation, and supports the conclusion that reduced AQP4-dependent water transport is responsible for defective neuroexcitation in AQP4 deficiency.

Aquaporins: important but elusive drug targets

“…AQP4 deficiency is associated with a slower rate of potassium reuptake by astrocytes following neuroexcitation 59,61 , which — as supported by mathematical modelling — may be related to a reduced electrochemical driving force for potassium reuptake caused by slowed astrocyte water uptake and contraction of the extracellular space 62 . AQP4-deficient mice also have impaired glial scar formation, which may be related to defective astrocyte migration 63,64 .…”

Astrogliosis

“…In the healthy CNS, astrocytes (1) maintain the extracellular homeostasis of K þ , water, pH, and transmitter uptake (Halassa and Haydon 2010;Jin et al 2013), (2) may modulate synaptic activity directly via release of "gliotransmitters" (Volterra and Meldolesi 2005;Halassa and Haydon 2010;Hamilton and Attwell 2010;Henneberger et al 2010), and (3) take part in the formation and pruning of synapses (Chung et al 2013;Clarke and Barres 2013). Functional changes undergone by reactive astrocytes in response to specific molecular triggers can impact neurons via (1) down-regulation of glutamine synthase associated with reduced inhibitory synaptic currents in local neurons (Ortinski et al 2010), (2) increased expression of xCT (Slc7a11), a cysteine-glutamate transporter associated with increased glutamate signaling, seizures, and excitotoxicity (Jackman et al 2010;Buckingham et al 2011), and (3) changes in the expression of multiple GPCRs and G proteins and calcium signaling evoked by their ligands (Hamby et al 2012).…”

Physiological Roles of Aquaporin-4 in Brain

“…This could contribute to the delayed K ϩ clearance observed in animals lacking ␣-syntrophin. A recent modeling study concluded that AQP4 can regulate K ϩ uptake through effects on extracellular volume (73).…”