title: 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 α-syntrophin (α-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 α-syn deletion on astrocyte morphology and changes in extracellular diffusion associated with cell swelling in vitro and in vivo. In mice lacking α-syn, we found higher resting values of the apparent diffusion coefficient of water (ADCW) and the extracellular volume fraction (α). No significant differences in tortuosity (λ) or non-specific uptake (k'), were found between α-syn-negative (α-syn -/-) and α-syn-positive (α-syn +/+) mice. The deletion of α-syn resulted in a significantly smaller relative decrease in α 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 α indicate milder cell swelling in α-syn -/- in comparison with α-syn +/+ mice. Shortly after terminal ischemia/anoxia induction, the onset of a steep rise in the extracellular potassium concentration and an increase in λ was faster in α-syn -/- mice, but the final values did not differ between α-syn -/- and α-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.
authors.affiliation: Institute of Experimental Medicine AS CR, v.v.i., Prague, Czech Republic.
authors.forename: Lesia
authors.initials: L
authors.lastname: Dmytrenko
authors.forename: Michal
authors.initials: M
authors.lastname: Cicanic
authors.forename: Miroslava
authors.initials: M
authors.lastname: Anderova
authors.forename: Ivan
authors.initials: I
authors.lastname: Vorisek
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Ottersen
authors.forename: Eva
authors.initials: E
authors.lastname: Sykova
authors.forename: Lydia
authors.initials: L
authors.lastname: Vargova
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004058:Diffusion; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D005838:Genotype; D006323:Heart Arrest / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D009997:Osmotic Pressure; D011188:Potassium / Q000378:metabolism; D013003:Somatosensory Cortex / Q000378:metabolism
chemical_list: D051401:Aquaporin 4; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; C091825:syntrophin alpha1; D011188:Potassium