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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