Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference

• Published in: Journal of cerebral blood flow and metabolism Vol. 31; no. 3; pp. 819 - 831
• Main Authors: Badaut, Jérôme, Ashwal, Stephen, Adami, Arash, Tone, Beatriz, Recker, Rebecca, Spagnoli, David, Ternon, Béatrice, Obenaus, Andre
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-03-2011; Nature Publishing Group; Sage Publications Ltd
• Subjects: Animals; Aquaporin 4; Aquaporin 4 - antagonists & inhibitors; Aquaporin 4 - genetics; Astrocytes - metabolism; Biological and medical sciences; Body Water - metabolism; Brain - metabolism; Cell membranes; Cell size; Cerebral blood flow; Diffusion; Diffusion coefficient; Embryo, Mammalian; Injuries; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Mice; Mobility; Molecular modelling; Nervous system; Neuroimaging; Neurology; Original; Plasma membranes; Prognosis; Rats; Rats, Sprague-Dawley; RNA Interference; RNA, Small Interfering; RNA-mediated interference; Spheroids, Cellular; Stroke; Tissue Culture Techniques; Transfection; Trauma; Ultrasonic investigative techniques; Vascular diseases and vascular malformations of the nervous system; apparent diffusion coefficient; edema; water channel; neuroimaging; neurovascular unit; Edema; Nervous system diseases; Central nervous system disease; Mobility; Diffusion coefficient; Cerebrovascular disease; Cerebral disorder; Encephalon
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2010.163

Neuroimaging with diffusion-weighted imaging is routinely used for clinical diagnosis/prognosis. Its quantitative parameter, the apparent diffusion coefficient (ADC), is thought to reflect water mobility in brain tissues. After injury, reduced ADC values are thought to be secondary to decreases in the extracellular space caused by cell swelling. However, the physiological mechanisms associated with such changes remain uncertain. Aquaporins (AQPs) facilitate water diffusion through the plasma membrane and provide a unique opportunity to examine the molecular mechanisms underlying water mobility. Because of this critical role and the recognition that brain AQP4 is distributed within astrocytic cell membranes, we hypothesized that AQP4 contributes to the regulation of water diffusion and variations in its expression would alter ADC values in normal brain. Using RNA interference in the rodent brain, we acutely knocked down AQP4 expression and observed that a 27% AQP4-specific silencing induced a 50% decrease in ADC values, without modification of tissue histology. Our results demonstrate that ADC values in normal brain are modulated by astrocytic AQP4. These findings have major clinical relevance as they suggest that imaging changes seen in acute neurologic disorders such as stroke and trauma are in part due to changes in tissue AQP4 levels.