Filtering the muddied waters of brain edema

Abstract

A central puzzle in our understanding of aquaporin 4 (AQP4) is the observation that paravascular astrocytic end-feet express abundant AQP4, whereas the cerebral microvessels they abut express tight junctions and no known aquaporins [ 1 Iliff J.J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 2012; 4: 147ra111 Crossref PubMed Scopus (2591) Google Scholar ]. Much of previous research exploring the role of AQP4 in water transport has focused on the tripartite synapse. This model places pre- and postsynaptic neuronal, and perisynaptic astrocyte processes as the central point initiating fluid movement [ 2 Papadopoulos M.C. Verkman A.S. Aquaporin water channels in the nervous system. Nat. Rev. Neurosci. 2013; 14: 265-277 Crossref PubMed Scopus (475) Google Scholar ]. Smith et al. suggest that osmotic gradients provide the dominant driving force for water movement, as a result of the large ion fluctuations that accompany neuronal activity, in small extracellular space (ECS) dimensions (Figure 1A) [ 3 Jin B.J. et al. Aquaporin-4-dependent K+ and water transport modeled in brain extracellular space following neuroexcitation. J. Gen. Physiol. 2013; 141: 119-132 Crossref PubMed Scopus (63) Google Scholar ]. However, most prior analyses that have highlighted the importance of synaptic transmission as the driver of fluid movement have used experimental preparations that eliminated global convective fluxes – such as open craniotomies, brain slices, and cell cultures – where the vascular and cerebrospinal fluid (CSF) compartments are invariably compromised [ 2 Papadopoulos M.C. Verkman A.S. Aquaporin water channels in the nervous system. Nat. Rev. Neurosci. 2013; 14: 265-277 Crossref PubMed Scopus (475) Google Scholar ]. In addition, AQP4 is not highly expressed in the tripartite synapse. Instead, astrocytes located both in grey and white matter (lacking the tripartite synapse) display nearly 10-fold higher AQP4 expression in paravascular processes and the glial limitans than on perisynaptic processes [ 4 Nagelhus E.A. Ottersen O.P. Physiological roles of aquaporin-4 in brain. Physiol. Rev. 2013; 93: 1543-1562 Crossref PubMed Scopus (406) Google Scholar ]. It is therefore perhaps unsurprising that selectively decreasing the paravascular pool of AQP4 without altering the overall level of AQP4 expression, recapitulates all of the known phenotypes seen in global AQP4 knock-out mice [ 4 Nagelhus E.A. Ottersen O.P. Physiological roles of aquaporin-4 in brain. Physiol. Rev. 2013; 93: 1543-1562 Crossref PubMed Scopus (406) Google Scholar ]. Using modeling or empirical data from only the perisynaptic region to infer what forces govern global solute and water movement, as Smith et al. suggest, is therefore inadequate and misleading [ 3 Jin B.J. et al. Aquaporin-4-dependent K+ and water transport modeled in brain extracellular space following neuroexcitation. J. Gen. Physiol. 2013; 141: 119-132 Crossref PubMed Scopus (63) Google Scholar ]. We instead propose that the highly polarized expression of AQP4 on astrocyte processes abutting paravascular and subarachnoid CSF strongly suggests that global interstitial fluid (ISF)–CSF exchange, rather than localized water and ion fluxes associated with synaptic activity, is the major function of AQP4 in the intact CNS (Figure 1B).