Anales RANF

S3-02 ROLE OF ASTROGLIAL PURINERGIC TRANSMISSION IN ALZHEIMER’S DISEASE N. Reichenbach 1 , A. Delekate 1 , B. Breithausen 1,2 , K. Keppler 1 , S. Poll 1 , T. Schulte 1 , J. Peter 1 , M. Plescher 1 , J.N. Hansen 1 , N. Blank 1 , A. Keller 1 , M. Fuhrmann 1 , C. Henneberger 1,2 , A. Halle 1,2 , G.C. Petzold 1,2 1 . German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 2 . University Hospital Bonn, Bonn, Germany. Alzheimer ́s disease (AD) is characterized by a progressive loss of memory and cognitive functions. One of the pathological hallmarks of AD is the extracellular deposition of plaques containing amyloid- β (A β ). We have shown that reactive astrocytes around plaques become hyperactive, which is mediated by purinergic signaling through the P2Y1 receptor, but the consequences of long-term treatment with a P2Y1 receptor antagonist for network activity, amyloid metabolism and behavior have remained undetermined. We administered the P2Y1 receptor antagonist MRS2179 intracerebroventricularly to APPPS1 mice for 6 weeks using osmotic minipumps. We recorded astroglial-neuronal network activity using in vivo two-photon microscopy of calcium indicators. Spatial learning and memory were tested using the Barnes Maze. Hippocampal long-term potentiation (LTP) was investigated in acute hippocampal slices. Plaque load, gliosis and soluble and insoluble amyloid levels were determined by immunohistochemical and biochemical analysis. We have found that chronic treatment normalized astroglial hyperactivity. Deficits in spatial learning and memory were significantly ameliorated by MRS2179. The LTP suppression found in hippocampal slices of APPPS1 mice was prevented by MRS2179. These effects occured without significant changes in plaque size or number. MRS2179 treatment also normalized network dysfunction, ameliorated cognitive abnormalities, and reduced synaptic dysfunction. Our data indicate that aberrant astrocytic network activity contributes to synaptic and cognitive deficits in mouse models of AD, and that purinoreceptor signalling may represent a potential therapeutic target for future translational studies. Finally, we describe a novel RNAseq-based approach enabling the identification of novel astroglial calcium pathways for future studies.