Cation Retention in Membrane Potential Wells: Ionic Microdomain Formation at the Perisynaptic Cradle

Recent studies have demonstrated that neuronal activity triggers transient increases in the cytosolic [Na+]PsC and [K+]PsC concentrations at the perisynaptic cradle (PsC). These microdomains strongly correlate with several crucial homeostatic pathways including K+ uptake by astrocytes and neuronal metabolic support. The aim of this poster is to present using mathematical modelling, a new hypothesis whereby microdomain formation is a direct result of fixed negatively charged ions associated with the dipole heads of membrane phospholipids. Specifically, we hypothesize that these negatively charged lipids result in deep potential wells near the dipole heads restricting the flow of cations in thin astrocyte processes to “hopping” between wells (well hopping) as they transverse the process. Results show that for very thin astrocyte processes, with a large surface to volume ratio, cation retention in wells dominates over conventional electrochemical diffusion (see Figure below). Essentially this low conductance pathway semi-isolates the PsC from the astrocytic soma allowing microdomains to form at the PsC. This has implications for K+ clearance as [K+]PsC microdomain acts as a “local store” for K+ to be returned to the ECS after neuronal excitation, thus preventing K+ undershoot . In particular, this could explain the slow decay rate of Na+ following a glutamate uptake through EAAT1/2. The formation of microdomains may have a pathological potential as alterations to the local intra- and extracellular homeostatic environment impairs neurotransmitters clearance from the synaptic cleft, therefore promoting network hyper-excitability.