Session 8 :

25TH EUROPEAN WINTER CONFERENCE ON BRAIN RESEARCH,
ARC 1800 - FRANCE, MARCH 5 - 12, 2005.

Title: Towards a molecular understanding of water transport in the brain: Role of aquaporins.

This is a timely subject, as explained below. An overview of the advances in this field was given in our recent paper in Nature Reviews Neuroscience
(Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci. 2003 Dec;4(12):991-1001). The timeliness of the subject is also emphasized by the selection of Dr Peter Agre - the discoverer of aquaporin water channels - as recipient of the Nobel Prize in Chemistry for 2003.

Insight in the mechanisms of water transport in brain has provided a better understanding of factors controlling neuronal excitability and of the pathogenesis of brain edema and other conditions characterized by a perturbation of water and ion homeostasis.

The overall objectives of the proposed symposium:

        Brain edema is a severe problem in the clinic and contributes significantly to the morbidity and mortality of a series of neurosurgical and neurological conditions including stroke. Currently, the treatment of edema is largely restricted to administration of hyperosmolar agents or surgical decompression  - therapies that were introduced early in the last century. Better and more rational therapies are urgently needed. The objective of the proposed symposium is to provide an update of recent breakthroughs in our understanding of the molecular basis of water transport in the brain and to discuss how this new insight could be used as a platform for novel and more efficient therapies in brain edema and other conditions of perturbed water and ion homeostasis. The symposium will cover the field of brain water transport, from molecules to the clinic. The major focus will be on the basic neurobiological aspects but the clinical perspectives will be emphasized by all speakers.

This field was opened by the seminal discovery, by Peter Agre (Nobel Laureate in Chemsitry 2003), of a membrane protein in red blood cells that allows a specific and high capacity transmembrane flux of water (Preston GM, Carroll TP, Guggino WB, Agre P. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science. 1992 Apr 17;256(5055):385-7). This membrane protein, named aquaporin 1, turned out to be the first member of a family of water channel proteins that is now thought to be responsible for rapid transmembrane water flux in most organs in the body.  By comparison, the diffusion of water through the lipid bilayer is a slow process and typically accounts for less than 1/1000 of the transmembrane water fluxing capacity.

Aquaporin 1 is strongly expressed in the kidney, as are several other members of the aquaporin family. However, in 1997, two of the participants of the proposed symposium (Nielsen and Ottersen with their collaborators) demonstrated by immunogold cytochemistry that the brain contains the water channel aquaporin-4 (AQP4) and that this channel is particularly abundant in those astrocyte membrane domains that face the pial membrane and cerebral microvessels- i.e., the membranes that constitute the interface between intra- and extracerebral liquid spaces (Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP., J Neurosci. 1997 Jan 1;17(1):171-80). We hypothesized in this study that the aquaporin-4 pool in these membrane domains are likely to control the rate by which water passes into and out of the brain and that aquaporin-4 could be a potential molecular target in the treatment of brain edema.

This notion has since received support by analyses of mice with deletions of the aquaporin-4 gene (Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS., Nat Med 2000 Feb;6(2):159-63) and by studies of mice lacking essential components of the molecular complex that normally serve to anchor aquaporin-4 to the specialized glial membrane domains at the brain-blood interface (Vajda Z, Pedersen M, Fuchtbauer EM, Wertz K, Stodkilde-Jorgensen H, Sulyok E, Doczi T, Neely JD, Agre P, Frokiaer J, Nielsen S., Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13131-6; Amiry-Moghaddam M, Otsuka T, Hurn P, Traystman RJ, Haug FM, Froehner SC, Adams ME, Neely JD, Agre P, Ottersen OP, Bhardwaj A., Proc Natl Acad Sci USA, 2003 Feb 18;100(4):2106-11). The latter studies were based on previous observations that the polarized expression of aquaporin-4 in astrocytes depends on dystrophin and alpha-syntrophin (Frigeri A, Nicchia GP, Nico B, Quondamatteo F, Herken R, Roncali L, Svelto M., FASEB J. 2001 Jan;15(1):90-98; Neely JD, Amiry-Moghaddam M, Ottersen OP, Froehner SC, Agre P, Adams ME. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14108-13).

The studies referred to above have greatly increased our understanding of the mechanisms underlying water and ion homeostasis in the brain. They have also provided support for the idea that aquaporin-4 may hold promise as a molecular target for therapy in brain edema. These prospects will be discussed in the proposed session.

Participants

Proposer
Ole Petter Ottersen, MD, PhD
Director, Centre for Molecular Biology and Neuroscience http://www.cmbn.no/
Professor, Department of Anatomy, University of Oslo
Centre for Molecular Biology and Neuroscience
Institute of Basic Medical Sciences,
University of Oslo
POB 1105 Blindern,
N-0317 Oslo, Norway

Anita Aperia, Professor of Pediatrics
Dept. of Woman and Child Health, Karolinska Institutet
Astrid Lindgren Children's Hospital, Q2:09
S-171 76 Stockholm, Sweden
Tel: +46-8-51777326 Fax: +46-8-51777328
E-mail: Anita.Aperia@kbh.ki.se

Søren Nielsen
Professor of Cell Biology and Pathophysiology
Director, The Water and Salt Research Center
Institute of Anatomy, Building 233/234
University of Aarhus
DK-8000 Aarhus
DENMARK
Phone: +45 89423046 / +45 23244533
FAX: +45 86198664
Email: sn@ana.au.dk
Web: http://www.waterandsalt.au.dk/

I have also invited Prof. Jørgen Frøkiær from the latter Center.

All the above participants have agreed to participate.

The session might be expanded as the organizers deem fit, for example by including Prof Antonio Frigeri, a young scientist from the University of Bari, Italy. He has been a central player in the field. Another young investigator might also be included: Mahmood Amiry-Moghaddam from the University of Oslo. He has published a series of landmark papers in the field over the past two years (FASEB J. 2004 Mar;18(3):542-4, Nat Rev Neurosci. 2003 Dec;4(12):991-1001, Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13615-20, Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2106-11).