Discussion
In this study, we have focused on establishing whether the modulation of α5 GABAAR-associated synaptic transmission by compounds with negative allosteric effects could be a successful targeted therapeutic strategy in Alzheimer’s disease (AD).
It has been evidenced that the GABAAR α subunits form a structural basis for the different pharmacological and thus, behavioural profiles of various allosteric modulators of these receptors (Mohler et al., 2002; Whiting, 2003). In particular, allosteric modulation of α5-containing GABAARs has been shown to gate the acquisition and modify the extinction of associative learning in animal models (Collinson et al., 2002; Crestani et al., 2002; Dawson et al., 2006; Yee et al., 2004), yet clinical trials aimed at alleviating cognitive deficits with selective negative allosteric modulators of these receptors have failed. Our objective in the current study was to resynthesize a hybrid compound of an established NAM, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, in order to increase its’ aqueous solubility, as well as its’ selectivity and potency as a negative allosteric modulator of α5 GABAARs. Inhibition mediated via these receptors is widespread in the brain but it is particularly abundant in the hippocampus (Magnin et al., 2019), where we have identified four sub-populations of neurons that express high levels of α5 GABAARs. Using the AppNL-F/NL-Fknock-in mouse model of AD, that shows an age-dependent increase in the main pathological hallmarks of this disease, including accumulation of Αβ, activation of microglia and reactive astrocytes and neurodegeneration (Shi et al., 2019), we have revealed how the negative allosteric modulation of α5 GABAARs canexacerbate the aberrant hyperexcitability and synaptic dysregulation in AD.