Aberrant remodelling of astrocytic architecture in acute hepatic encephalopathy: complexity of oedematic atrophic astrocytes

Hepatic encephalopathy (HE) following acute liver failure (ALF) is a primary toxic astrocytopathy, although in-depth characterisation of underlying pathogenesis is far from complete. Among the multitude of astrocyte-specific proteins guiding brain functionality, plasmalemma-cytoskeletal linker ezrin, actin-binding protein profilin-1, and water channel aquaporin 4 (AQP4) contribute to astrocytic morphological plasticity through regulation of cell shape, volume, complexity of primary and terminal processes, and positioning astrocytes against other CNS constituents. Changes in these proteins might contribute to the brain oedema and astrocytic morphological remodelling in the HE. Using transmission electron microscopy, confocal fluorescent microscopy, and 3D reconstruction, we found complex morphological alterations of cortical astrocytes in mice with azoxymethane-induced ALF. Astrocytic primary branches demonstrated hypertrophy, whereas terminal leaflets showed atrophy quantified by the reduced area occupied by astrocytes, decreased number and the length of leaflets, decreased leaflets volume fraction, and altered astrocyte-to-neurone landscape. These morphological changes correlat with decreased expression of AQP4, phosphorylated leaflet-associated ezrin, and the actin dynamics regulator, profilin 1, suggesting the contribution of these proteins to astrocytic pathological remodelling. Pathological changes in astrocytes develop in parallel, and are likely causally linked to, the HE-linked neurological decline, manifested by a reduction in electroencephalography power and by excessive glutamate in the brain microdialysates. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/602491v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@45d6a3org.highwire.dtl.DTLVardef@10e9ac3org.highwire.dtl.DTLVardef@1d28b36org.highwire.dtl.DTLVardef@1b1b866_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract:C_FLOATNO Hepatic encephalopathy is associated with astrocyte remodelling manifested by swelling of the soma and primary branches together with atrophy of distal branches and leaflets; the latter retract from synapses thus affecting neurotransmission and contribute to the reduced neuronal activity. Astrocyte remodelling was linked to (and probably instigated by) a decrease of plasmalemma-cytoskeleton linker phosphorylated ezrin (Phos-ezrin), actin modulator profilin-1 (PFN1) and water channel aquaporin 4 (AQP4). C_FIG