Abstract
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 change in the expression of α5 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 α5 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-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. In aged APPNL−F/NL−F mice, 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, 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 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. In summary, 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.
Highlights
Over the last few decades, considerable focus has been on negative allosteric modulators (NAMs; previously referred to as inverse agonists) of the benzodiazepine site of γ-aminobutyric acid receptors (GABAARs) as a potential therapeutic target for cognitive impairment in temporal lobe epilepsy (TLE), Huntington’s disease, Down’s syndrome, schizophrenia and the most common form of dementia, Alzheimer’s disease (AD), which constitutes one of the most significant health problems confronting societies with an aging population.The ionotropic GABAAR family are heteropentameric structures consisting of a combination of five subunits (Sieghart and Sperk, 2002) with the α–subunit being clinically relevant, as it controls the pharmacological profile of GABAA Rs (McKernan and Whiting, 1996)
We have shown that this modulator can ‘‘normalize’’ abnormal, inhibitory synaptic activity received by CR interneurons in this model, suggesting initially its’ therapeutic potential
Since our data suggest that α5 GABAARs are widely expressed by both dysfunctional and resilient neurons, and that α5SOP002 can compromise further the aberrant hyperexcitable network in the AD model, we propose that pharmacological modulation of α5 subunit-containing GABAAR networks may not be a suitable therapeutic target for cognitive impairment in AD
Summary
Over the last few decades, considerable focus has been on negative allosteric modulators (NAMs; previously referred to as inverse agonists) of the benzodiazepine site of γ-aminobutyric acid receptors (GABAARs) as a potential therapeutic target for cognitive impairment in temporal lobe epilepsy (TLE), Huntington’s disease, Down’s syndrome, schizophrenia and the most common form of dementia, Alzheimer’s disease (AD), which constitutes one of the most significant health problems confronting societies with an aging population.The ionotropic GABAAR family are heteropentameric structures consisting of a combination of five subunits (Sieghart and Sperk, 2002) with the α–subunit being clinically relevant, as it controls the pharmacological profile of GABAA Rs (McKernan and Whiting, 1996). Since the understanding that distinct pharmacological properties of the GABAAR are reliant on the fact that different brain regions and cell types contain various subunit compositions, NAMs of the GABAAR at the subunit level have been widely studied. The strong evidence to suggest hippocampal preferential distribution of the α5-containing GABAAR sub-type (Quirk et al, 1996), together with its diverse pathology in memory deficit-related disease, and its preservation in human brains of AD patients (Howell et al, 2000; Rissman et al, 2007), has led many researchers to test several α5 subunit-selective compounds for their potential cognition-enhancing effects (Liu et al, 1996; Quirk et al, 1996; Sternfeld et al, 2004; Savic et al, 2008)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
