Selective Modulation of α5 GABAA Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimer’s Disease

Selective negative allosteric modulators (NAMs), targeting 5 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 change in of the expression of 5 GABAARs, consequently altering synaptic function during AD pathogenesis. 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 5 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, 5-SOP002 in the hippocampal CA1 region. In aged APPNL-F/NL-F mice, a selective preservation of α5 GABAARs was observed in, calretinin- (CR), cholecystokinin- (CCK), somatostatin- (SST) expressing interneurons, and pyramidal cells. Previously, we reported that CR dis-inhibitory interneurons, specialised in regulating other interneurons displayed abnormally high levels of synaptic inhibition in the APPNL-F/NL-F mouse model, here we show that this excessive inhibition was “normalised” to control values with bath-applied 5-SOP002 (1 M). However, 5-SOP002, further impaired inhibition onto CCK and pyramidal cells that were already largely compromised by exhibiting a deficit of inhibition in the AD model. In summary, using a multi-disciplinary approach, we show that exposure to 5 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 5 GABAARs.