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.