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Abstract #0353

Diminishing GABA A alpha5 receptor mediated inhibition rescues hippocampal perfusion deficit in a mouse model of Down syndrome

Thomas Mueggler 1 , Michael Honer 1 , Basil Knnecke 1 , Andreas Bruns 1 , Andrew W. Thomas 2 , Maria-Clemencia Hernandez 1 , and Markus von Kienlin 1

1 Pharma Research & Early Development, DTA Neuroscience, Hoffmann-La Roche, Basel, Basel-City, Switzerland, 2 Pharma Research & Early Development, Pharma Research & Early Development, Small Molecule Research, Hoffmann-La Roche, Basel, Basel-City, Switzerland

Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of Down syndrome. Using ASL-based fMRI we reveal a region-specific perfusion phenotype in TS mice and demonstrate complete reversal after chronic treatment with RO4938581, a negative allosteric modulator (NAM) selective for the GABA A alpha5 receptor subtype, specifically of the observed hippocampal deficits. This novel finding is in line with recently reported effects of RO4938581 to rescue hippocampal synaptic plasticity, spatial learning and memory in TS mice supporting the potential therapeutic use of selective GABA A alpha5 NAMs to treat cognitive dysfunction in Down syndrome.

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