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).