TY - JOUR

T1 - Activity-dependent astrocyte swelling is mediated by pH-regulating mechanisms

AU - Larsen, Brian Roland

AU - MacAulay, Nanna

N1 - © 2017 Wiley Periodicals, Inc.

PY - 2017/10

Y1 - 2017/10

N2 - During neuronal activity in the mammalian brain, the K(+) released into the synaptic space is initially buffered by the astrocytic compartment. In parallel, the extracellular space (ECS) shrinks, presumably due to astrocytic cell swelling. With the Na(+) /K(+) /2Cl(-) cotransporter and the Kir4.1/AQP4 complex not required for the astrocytic cell swelling in the hippocampus, the molecular mechanisms underlying the activity-dependent ECS shrinkage have remained unresolved. To identify these molecular mechanisms, we employed ion-sensitive microelectrodes to measure changes in ECS, [K(+) ]o and [H(+) ]o /pHo during electrical stimulation of rat hippocampal slices. Transporters and receptors responding directly to the K(+) and glutamate released into the extracellular space (the K(+) /Cl(-) cotransporter, KCC, glutamate transporters and G protein-coupled receptors) did not modulate the extracellular space dynamics. The HCO3--transporting mechanism, which in astrocytes mainly constitutes the electrogenic Na(+) / HCO3- cotransporter 1 (NBCe1), is activated by the K(+) -mediated depolarization of the astrocytic membrane. Inhibition of this transporter reduced the ECS shrinkage by ∼25% without affecting the K(+) transients, pointing to NBCe1 as a key contributor to the stimulus-induced astrocytic cell swelling. Inhibition of the monocarboxylate cotransporters (MCT), like-wise, reduced the ECS shrinkage by ∼25% without compromising the K(+) transients. Isosmotic reduction of extracellular Cl(-) revealed a requirement for this ion in parts of the ECS shrinkage. Taken together, the stimulus-evoked astrocytic cell swelling does not appear to occur as a direct effect of the K(+) clearance, as earlier proposed, but partly via the pH-regulating transport mechanisms activated by the K(+) -induced astrocytic depolarization and the activity-dependent metabolism.

AB - During neuronal activity in the mammalian brain, the K(+) released into the synaptic space is initially buffered by the astrocytic compartment. In parallel, the extracellular space (ECS) shrinks, presumably due to astrocytic cell swelling. With the Na(+) /K(+) /2Cl(-) cotransporter and the Kir4.1/AQP4 complex not required for the astrocytic cell swelling in the hippocampus, the molecular mechanisms underlying the activity-dependent ECS shrinkage have remained unresolved. To identify these molecular mechanisms, we employed ion-sensitive microelectrodes to measure changes in ECS, [K(+) ]o and [H(+) ]o /pHo during electrical stimulation of rat hippocampal slices. Transporters and receptors responding directly to the K(+) and glutamate released into the extracellular space (the K(+) /Cl(-) cotransporter, KCC, glutamate transporters and G protein-coupled receptors) did not modulate the extracellular space dynamics. The HCO3--transporting mechanism, which in astrocytes mainly constitutes the electrogenic Na(+) / HCO3- cotransporter 1 (NBCe1), is activated by the K(+) -mediated depolarization of the astrocytic membrane. Inhibition of this transporter reduced the ECS shrinkage by ∼25% without affecting the K(+) transients, pointing to NBCe1 as a key contributor to the stimulus-induced astrocytic cell swelling. Inhibition of the monocarboxylate cotransporters (MCT), like-wise, reduced the ECS shrinkage by ∼25% without compromising the K(+) transients. Isosmotic reduction of extracellular Cl(-) revealed a requirement for this ion in parts of the ECS shrinkage. Taken together, the stimulus-evoked astrocytic cell swelling does not appear to occur as a direct effect of the K(+) clearance, as earlier proposed, but partly via the pH-regulating transport mechanisms activated by the K(+) -induced astrocytic depolarization and the activity-dependent metabolism.

U2 - 10.1002/glia.23187

DO - 10.1002/glia.23187

M3 - Journal article

C2 - 28744903

VL - 65

SP - 1668

EP - 1681

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 10

ER -