loading page

Selective modulation of α5 GABAA receptors exacerbates aberrant inhibition at key hippocampal neuronal circuits in APP mouse model of Alzheimer’s disease
  • +6
  • Alexandra Petrache,
  • Archie Khan,
  • Martin Nicholson,
  • Alessandra Monaco,
  • Martyna Kuta-Siejkowska ,
  • Shozeb Haider,
  • Stephen Hilton,
  • Jasmina Jovanovic,
  • Afia Ali
Alexandra Petrache
University College London School of Pharmacy
Author Profile
Archie Khan
University College London School of Pharmacy
Author Profile
Martin Nicholson
University College London School of Pharmacy
Author Profile
Alessandra Monaco
University College London School of Pharmacy
Author Profile
Martyna Kuta-Siejkowska
University College London School of Pharmacy
Author Profile
Shozeb Haider
University College London School of Pharmacy
Author Profile
Stephen Hilton
University College London School of Pharmacy
Author Profile
Jasmina Jovanovic
University College London School of Pharmacy
Author Profile
Afia Ali
University College London School of Pharmacy
Author Profile

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.