TY  - JOUR
AV  - public
Y1  - 2020/11/11/
VL  - 14
TI  - Selective Modulation of ?5 GABAA Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimer?s Disease
N1  - © 2020 Petrache, Khan, Nicholson, Monaco, Kuta-Siejkowska, Haider, Hilton, Jovanovic and Ali. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
PB  - Frontiers Media
UR  - https://doi.org/10.3389/fncel.2020.568194
ID  - discovery10111175
N2  - 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 the expression of ?5 GABAARs, consequently altering synaptic function during AD pathogenesis. Using medicinal chemistry and computational modeling, we developed aqueous soluble hybrids of 6,6-dimethyl-3-(2-hydroxyethyl) thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophene-4(5H)-one, that demonstrated selective binding and high negative allosteric modulation, specifically for the ?5 GABAAR subtypes 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-? (A?), 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, selective preservation of ?5 GABAARs was observed in, calretinin- (CR), cholecystokinin- (CCK), somatostatin- (SST) expressing interneurons, and pyramidal cells. Previously, we reported that CR dis-inhibitory interneurons, specialized 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 ?normalized? 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 ?5 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.
KW  - Alzheimer?s disease
KW  -  GABAA receptors
KW  -  synaptic
KW  -  interneurons
KW  -  hippocampus
A1  - Petrache, AL
A1  - Khan, AA
A1  - Nicholson, MW
A1  - Monaco, A
A1  - Kuta-Siejkowska, M
A1  - Haider, S
A1  - Hilton, S
A1  - Jovanovic, J
A1  - Ali, A
JF  - Frontiers in Cellular Neuroscience
ER  -