The Impact of Alpha-Syntrophin Deletion on the Changes in Tissue Structure and Extracellular Diffusion Associated with Cell Swelling under Physiological and Pathological Conditions

Aquaporin-4 (AQP4) is the primary cellular water channel in the brain and is abundantly expressed by astrocytes along the blood-brain barrier and brain-cerebrospinal fluid interfaces. Water transport via AQP4 contributes to the activity-dependent volume changes of the extracellular space (ECS), which affect extracellular solute concentrations and neuronal excitability. AQP4 is anchored by a-syntrophin (a-syn), the deletion of which leads to reduced AQP4 levels in perivascular and subpial membranes. We used the real-time iontophoretic method and/or diffusion-weighted magnetic resonance imaging to clarify the impact of a-syn deletion on astrocyte morphology and changes in extracellular diffusion associated with cell swelling in vitro and in vivo. In mice lacking a-syn, we found higher resting values of the apparent diffusion coefficient of water (ADCW) and the extracellular volume fraction (a). No significant differences in tortuosity (l) or non-specific uptake (k9), were found between a-syn-negative (a-syn 2/2) and a-syn-positive (a-syn +/+) mice. The deletion of a-syn resulted in a significantly smaller relative decrease in a observed during elevated K+ (10 mM) and severe hypotonic stress (2100 mOsmol/l), but not during mild hypotonic stress (250 mOsmol/l). After the induction of terminal ischemia/anoxia, the final values of ADCW as well as of the ECS volume fraction a indicate milder cell swelling in a-syn 2/2 in comparison with a-syn +/+ mice. Shortly after terminal ischemia/anoxia induction, the onset of a steep rise in the extracellular potassium concentration and an increase in l was faster in a-syn 2/2 mice, but the final values did not differ between a-syn2/2 an