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Selective Modulation of ?5 GABA_A Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimer's Disease.

ABSTRACT: Selective negative allosteric modulators (NAMs), targeting ?5 subunit-containing GABA_A receptors (GABA_ARs) 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 GABA_ARs, 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 GABA_AR subtypes in constructed HEK293 stable cell-lines. Using a knock-in mouse model of AD (APP ^NL-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 APP ^NL-F/NL-F mice, selective preservation of ?5 GABA_ARs 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 APP ^NL-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 GABA_AR NAMs may further compromise aberrant synapses in AD. We, therefore, suggest that the ?5 GABA_AR is not a suitable therapeutic target for the treatment of AD or other cognitive deficits due to the widespread neuronal-networks that use ?5 GABA_ARs.

SUBMITTER: Petrache AL

PROVIDER: S-EPMC7686552 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Petrache Alexandra L AL Khan Archie A AA Nicholson Martin W MW Monaco Alessandra A Kuta-Siejkowska Martyna M Haider Shozeb S Hilton Stephen S Jovanovic Jasmina N JN Ali Afia B AB

Frontiers in cellular neuroscience 20201111

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 de ...[more]

PMID: 33262690

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Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a progressive cognitive decline. Epidemiological studies have suggested a protective role of caffeine consumption against age-related cognitive impairments and the risk of developing AD. Effects of caffeine have been particularly ascribed to its ability to block adenosine A2A receptors (A2ARs). Early pathological upregulation of these receptors by neurons is thought to be involved in the development of synaptic and memory deficits in AD but this remains ill-defined. To tackle this question, we employed a novel transgenic mouse model allowing to promote a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice, developing AD-like amyloidogenesis. This new model was used to determine the impact of an early upregulation of A2AR on the progression of neuropathological lesions, associated behavior and underlying mechanisms in APP/PS1 mice. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioral changes were not linked to major change in the development of amyloid pathology but rather associate with an increased p-tau at neuritic plaques. Moreover, proteomic and transcriptomic analysis coupled to quantitative immunofluorescence studies indicated that neuronal impairment of the receptor promoted both neuronal- and non-neuronal autonomous alterations i.e. loss of excitatory synapses and neuroinflammatory response, respectively, both presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction as seen in the brain of patients contributes to AD pathogenesis, favoring synaptic deficits promoted by both amyloid (this study) and tau lesions (our previous study). In addition to provide new insights into the complex pathophysiology of AD, the present findings underscore the potential of A2AR as a relevant therapeutic target for mitigating early synaptic loss in this neurodegenerative disorder.

Dataset Information

Selective Modulation of ?5 GABA_A Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimer's Disease.

Publications

Selective Modulation of α5 GABA<sub>A</sub> Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in <i>APP</i> Mouse Model of Alzheimer's Disease.

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Dataset Information

Selective Modulation of ?5 GABAA Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimer's Disease.

Publications

Selective Modulation of α5 GABA<sub>A</sub> Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in <i>APP</i> Mouse Model of Alzheimer's Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Selective Modulation of ?5 GABA_A Receptors Exacerbates Aberrant Inhibition at Key Hippocampal Neuronal Circuits in APP Mouse Model of Alzheimer's Disease.