Selective modulation of α5 GABAA receptors exacerbates aberrant
inhibition at key hippocampal neuronal circuits in APP mouse model of
Alzheimer’s disease
Abstract
Background and Purpose: Selective negative allosteric modulators (NAMs),
targeting α5 subunit-containing GABAA receptors (GABAARs) as potential
therapeutic targets for disorders associated with cognitive deficits,
including Alzheimer’s disease (AD), continually fail clinical trials. We
investigated whether this was due to the alteration of synaptic
mechanisms associated with α5 GABAARs in AD. Experimental approach:
Using medicinal chemistry and computational modelling, we developed
aqueous soluble hybrids of
6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one,
that demonstrated selective binding and high negative allosteric
modulation, specifically for the α5 GABAAR subtype in constructed HEK293
stable cell-lines. Using a knock-in mouse model of AD (APPNL-F/NL-F),
which expresses a mutant form of human amyloid-β (Aβ), we performed
immunofluorescence studies combined with electrophysiological whole-cell
recordings to investigate the effects of our key molecule, α5-SOP002 in
the hippocampal CA1 region. Key Results: In aged APPNL-F/NL-F mice, a
selective preservation of α5 GABAARs was observed in: dis-inhibitory,
calretinin- (CR), cholecystokinin- (CCK), somatostatin- (SST) expressing
interneurons, and pyramidal cells. Synaptic inhibition recorded from CR
interneurons in APPNL-F/NL-F mice, was abnormally excessive, but was
“normalised” with bath-applied α5-SOP002 (1 μM). However, α5-SOP002,
further impaired inhibition onto CCK and pyramidal cells that were
already largely compromised by exhibiting a deficit of inhibition in the
AD model. Conclusions and Implications: Using a multi-disciplinary
approach, we show that exposure to α5 GABAAR NAMs may further compromise
aberrant synapses in AD. We therefore suggest that the α5 GABAAR is not
a suitable therapeutic target for the treatment of AD or other cognitive
deficits due to the widespread neuronal-networks that use α5 GABAARs.