Negative allosteric modulation of α5 subunit-containing
GABAARs further exacerbates hyperexcited synapses in the
AD model
As previously described, there is a gradual decline in the number of
CCK-SCA interneurons and CaMKII- expressing pyramidal cells in aged AD
mice, with the later showing hyperexcitability when the pathological
hallmarks of AD were present, clearly indicating the abnormalities in
neuronal network activity (Shi et al., 2019). Since these cells express
the α5 subunit, it is not surprising that α5-SOP002 can reduce
inhibition at CCK and pyramidal cells, and therefore exacerbate
imbalance between the excitation and inhibition at these key neuronal
populations in CA1 and impact on the efficacy and precision of the
fine-tuning inhibition at both temporal and spatial domains. These are
reasonable assumptions, since; CCK-SCA cells, which are ideally
positioned to modulate CA3 input, (Iball et al., 2011), and are
important for fine-tuning individual neurons by retrograde cannabinoid
signalling (Ali, 2007; Katona et al., 1999), whereas the SST, that
fine-tune distal inputs received by CA1 pyramidal cells (Leao et al.,
2012; Magnin et al., 2019), and are important for coordinating neuronal
assemblies and gating of memory formation (Cutsuridis et al., 2009; Tort
et al., 2007). Due to the prime location of these interneurons, it is
feasible to suggest that both of these interneuron sub-populations may
be involved in routing information flow to CA1 from CA3 and entorhinal
cortex- pathways that are important for memory acquisition and
retrieval, and their destruction during the pathogenesis of AD may be a
significant contributing factor to cognitive decline. This is further
supported by recent studies that show SST interneuron dysfunction
triggered by amyloid β oligomers underlies hippocampal oscillation
important for memory functions (Chung et al., 2020).