Honey, I shrunk the extracellular space: Measurements and mechanisms of astrocyte swelling

Abstract

Astrocyte volume fluctuation is a physiological phenomenon tied closely to the activation of neural circuits. Identification of underlying mechanisms has been challenging due in part to use of a wide range of experimental approaches that vary between research groups. Here, we first review the many methods that have been used to measure astrocyte volume changes directly or indirectly. While the field has recently shifted towards volume analysis using fluorescence microscopy to record cell volume changes directly, established metrics corresponding to extracellular space dynamics have also yielded valuable insights. We then turn to analysis of mechanisms of astrocyte swelling derived from many studies, with a focus on volume changes tied to increases in extracellular potassium concentration ([K + ] o ). The diverse methods that have been utilized to generate the external [K + ] o environment highlight multiple scenarios of astrocyte swelling mediated by different mechanisms. Classical potassium buffering theories are tempered by many recent studies that point to different swelling pathways optimized at particular [K + ] o and that depend on local/transient versus more sustained increases in [K + ] o .

Comparative analysis of hippocampal extracellular space uncovers widely altered peptidome upon epileptic seizure in urethane-anaesthetized rats

“…In 4-AP-induced seizures, astrocyte swelling was observed 2 h post-treatment, which can contribute to impaired metabolite and neurotransmitter clearance from brain ECF [ 17 ]. Astrocyte swelling also can reduce ECF volume [ 76 ]. A major water channel protein of astrocytes, Aqp4, regulates brain water homeostasis and ECF clearance.…”

Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex

“…This observation may explain an increase in extracellular space with age 9 , 26 . Astrocytic morphological changes are fundamental for the regulation of extracellular space 27 . An increase in extracellular space can also affect the extracellular diffusion of neurotransmitters, neuromodulators, and ions, as well as the operation of the glymphatic system 28 .…”

Aging impairs astrocytes in the human cerebral cortex

“…This observation may explain an increase in extracellular space with age (Salminen et al ., 2016, Verkhratsky et al ., 2021). Astrocytic morphological changes are fundamental for the regulation of extracellular space (Walch & Fiacco, 2022). An increase in extracellular space can also affect the extracellular diffusion of neurotransmitters, neuromodulators, and ions, as well as the operation of the glymphatic system (Benveniste et al ., 2019).…”