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

Area of Science:

• Neuroscience
• Cellular Physiology
• Astrocyte Biology

Background:

• Neuronal activity releases potassium (K+) into the synaptic space, buffered by astrocytes.
• Extracellular space (ECS) shrinkage, linked to astrocytic swelling, occurs during neuronal activity.
• Previous understanding did not identify molecular mechanisms for activity-dependent ECS shrinkage in the hippocampus.

Purpose of the Study:

• To identify the molecular mechanisms responsible for activity-dependent ECS shrinkage in the hippocampus.
• To investigate the role of specific transporters and ions in astrocytic swelling and ECS dynamics.

Main Methods:

• Used ion-sensitive microelectrodes to measure ECS, extracellular potassium ([K+]o), and extracellular pH ([H+]o/pHo) in rat hippocampal slices.
• Electrically stimulated hippocampal slices to induce neuronal activity and measure transporter function.
• Inhibited key transporters (NBCe1, MCTs) and altered extracellular chloride (Cl-) concentrations to assess their impact on ECS dynamics.

Main Results:

• Inhibition of the electrogenic sodium-bicarbonate cotransporter 1 (NBCe1) reduced ECS shrinkage by approximately 25%, without affecting potassium transients.
• Inhibition of monocarboxylate cotransporters (MCTs) also reduced ECS shrinkage by approximately 25%, without affecting potassium transients.
• Reduced extracellular chloride partially contributed to ECS shrinkage, and pH-regulating mechanisms were activated by K+-induced astrocytic depolarization.

Conclusions:

• Activity-dependent astrocytic cell swelling and ECS shrinkage are not a direct consequence of potassium clearance.
• The Na+/HCO3- cotransporter 1 (NBCe1) and monocarboxylate cotransporters (MCTs) are key contributors to stimulus-induced astrocytic swelling.
• pH-regulating transport mechanisms, activated by K+-induced astrocytic depolarization and metabolic activity, play a significant role in ECS shrinkage.