Aquaporin-4-Deficient Mice Have Increased Extracellular Space without Tortuosity Change

Yao, Xiaoming; Hrabětová, Sabina; Nicholson, Charles; Manley, Geoffrey T.

doi:10.1523/jneurosci.0257-08.2008

Cited by 136 publications

(132 citation statements)

References 30 publications

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“…In accord with our finding of increased seizure susceptibility and reduced ECS volume in Has3 Ϫ/Ϫ mice, decreased seizure susceptibility and enlarged ECS volume were previously reported in aquaporin-4-deficient mice (Binder et al, 2004;Yao et al, 2008). We also note that other studies have demonstrated modulation of ongoing epileptiform activity by osmotically induced ECS volume changes (Andrew et al, 1989;Traynelis and Dingledine, 1989;Dudek et al, 1998).…”

Section: Discussionsupporting

confidence: 92%

Hyaluronan Deficiency Due toHas3Knock-Out Causes Altered Neuronal Activity and Seizures via Reduction in Brain Extracellular Space

et al. 2014

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Hyaluronan (HA), a large anionic polysaccharide (glycosaminoglycan), is a major constituent of the extracellular matrix of the adult brain. To address its function, we examined the neurophysiology of knock-out mice deficient in hyaluronan synthase (Has) genes. Here we report that these Has mutant mice are prone to epileptic seizures, and that in Has3 Ϫ/Ϫ mice, this phenotype is likely derived from a reduction in the size of the brain extracellular space (ECS). Among the three Has knock-out models, namely Has3, and Has2 CKO , the seizures were most prevalent in Has3 Ϫ/Ϫ mice, which also showed the greatest HA reduction in the hippocampus. Electrophysiology in Has3Ϫ/Ϫ brain slices demonstrated spontaneous epileptiform activity in CA1 pyramidal neurons, while histological analysis revealed an increase in cell packing in the CA1 stratum pyramidale. Imaging of the diffusion of a fluorescent marker revealed that the transit of molecules through the ECS of this layer was reduced. Quantitative analysis of ECS by the real-time iontophoretic method demonstrated that ECS volume was selectively reduced in the stratum pyramidale by ϳ40% in Has3 Ϫ/Ϫ mice. Finally, osmotic manipulation experiments in brain slices from Has3 Ϫ/Ϫ and wild-type mice provided evidence for a causal link between ECS volume and epileptiform activity. Our results provide the first direct evidence for the physiological role of HA in the regulation of ECS volume, and suggest that HA-based preservation of ECS volume may offer a novel avenue for development of antiepileptogenic treatments.

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Section: Discussionsupporting

confidence: 92%

Hyaluronan Deficiency Due toHas3Knock-Out Causes Altered Neuronal Activity and Seizures via Reduction in Brain Extracellular Space

et al. 2014

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“…Thus, the increased brain water content must reflect excess water in brain parenchyma rather than any difference in ventricular volume. If glial-conditional Aqp4 −/− animals show an increase in baseline extracellular space volume similar to that reported for constitutive Aqp4 −/− (22,23), this would explain the excess water content.…”

Section: Discussionmentioning

confidence: 54%

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

Haj-Yasein

Vindedal

Eilert-Olsen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

285

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Tissue-and cell-specific deletion of the Aqp4 gene is required to differentiate between the numerous pools of aquaporin-4 (AQP4) water channels. A glial-conditional Aqp4 knockout mouse line was generated to resolve whether astroglial AQP4 controls water exchange across the blood-brain interface. The conditional knockout was driven by the glial fibrillary acidic protein promoter. Brains from conditional Aqp4 knockouts were devoid of AQP4 as assessed by Western blots, ruling out the presence of a significant endothelial pool of AQP4. In agreement, immunofluorescence analysis of cryostate sections and quantitative immunogold analysis of ultrathin sections revealed no AQP4 signals in capillary endothelia. Compared with litter controls, glial-conditional Aqp4 knockout mice showed a 31% reduction in brain water uptake after systemic hypoosmotic stress and a delayed postnatal resorption of brain water. Deletion of astroglial Aqp4 did not affect the barrier function to macromolecules. Our data suggest that the blood-brain barrier (BBB) is more complex than anticipated. Notably, under certain conditions, the astrocyte covering of brain microvessels is rate limiting to water movement. edema | electron microscopy | homeostasis | membrane | swelling M ore than 100 y have elapsed since it was first shown that some solutes present in blood are retained by brain capillaries, pointing to the existence of a barrier function at the bloodbrain interface. This early finding naturally inspired a discussion as to what could constitute the morphological substrate of this barrier (1). With the advent of the electron microscope it became clear that the blood-brain interface is composed of endothelia and pericytes, surrounded by a basal lamina and perivascular endfeet of astrocytes. After decades of intense debate, a concept emerged that the functional barrier resides at the level of the endothelial cells (2). This was consistent with morphological data, which clearly showed that endothelia were continuous and coupled by tight junctions (3). The perivascular endfeet, on the other hand, were not coupled by tight junctions and were portrayed as a discontinuous layer with spacious clefts separating the individual processes.Discussions on the morphological substrate of barrier function have been focused on solutes (4), and the field has not yet matured to provide a consistent view regarding what cellular structures, if any, restrict water movement between blood and brain. Following the discovery of water channels, it became clear that the major brain water channel AQP4 is implicated in water transport at the blood-brain interface. Thus, global Aqp4 knockout significantly limited the development of brain edema, attesting to the importance of AQP4 water channels (4). As AQP4 is strongly expressed in the perivascular endfeet (5), the interest in these processes was rekindled also in the context of their possible barrier function.Specifically, it was proposed that the endfeet could restrict water flow, most significantly in pathophysiological se...

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“…Aquaporins clearly do play diverse roles in brain water balance in health and disease [9,84] and such concepts have undoubtedly informed the 'glymphatic' hypothesis. The previous studies performed on AQP4-deficient mice have demonstrated that such animals exhibit an increased brain ECS volume fraction [196], increased basal brain water content [73], and larger intracranial pressure elevations in response to induced vasogenic (non-cellular) oedema [134], suggesting that AQP4 indeed plays critical roles in the transport of water between brain compartments as well as the formation and resolution of oedema. The key question for the 'glymphatic' concept is just what role astrocytic AQP4 may play in the circulation of fluid in perivascular compartments and how its deletion affects such circulation.…”

Section: Blood Vessels and The Perivascular Spacementioning

confidence: 99%

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

et al. 2018

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Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.

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Aquaporin-4-Deficient Mice Have Increased Extracellular Space without Tortuosity Change

Cited by 136 publications

References 30 publications

Hyaluronan Deficiency Due toHas3Knock-Out Causes Altered Neuronal Activity and Seizures via Reduction in Brain Extracellular Space

Hyaluronan Deficiency Due toHas3Knock-Out Causes Altered Neuronal Activity and Seizures via Reduction in Brain Extracellular Space

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

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