The impact of alpha-syntrophin deletion on the changes in tissue structure and extracellular diffusion associated with cell swelling under physiological and pathological conditions.

ABSTRACT: 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 ?-syntrophin (?-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 ?-syn deletion on astrocyte morphology and changes in extracellular diffusion associated with cell swelling in vitro and in vivo. In mice lacking ?-syn, we found higher resting values of the apparent diffusion coefficient of water (ADCW) and the extracellular volume fraction (?). No significant differences in tortuosity (?) or non-specific uptake (k'), were found between ?-syn-negative (?-syn -/-) and ?-syn-positive (?-syn +/+) mice. The deletion of ?-syn resulted in a significantly smaller relative decrease in ? observed during elevated K(+) (10 mM) and severe hypotonic stress (-100 mOsmol/l), but not during mild hypotonic stress (-50 mOsmol/l). After the induction of terminal ischemia/anoxia, the final values of ADCW as well as of the ECS volume fraction ? indicate milder cell swelling in ?-syn -/- in comparison with ?-syn +/+ mice. Shortly after terminal ischemia/anoxia induction, the onset of a steep rise in the extracellular potassium concentration and an increase in ? was faster in ?-syn -/- mice, but the final values did not differ between ?-syn -/- and ?-syn +/+ mice. This study reveals that water transport through AQP4 channels enhances and accelerates astrocyte swelling. The substantially altered ECS diffusion parameters will likely affect the movement of neuroactive substances and/or trophic factors, which in turn may modulate the extent of tissue damage and/or drug distribution.

SUBMITTER: Dmytrenko L 

PROVIDER: S-EPMC3702576 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature