Aberrant inhibition in CR interneurons is “normalised” by α5-SOP002 in the AD model
Previously, we reported that the CR interneuron network was “preserved” in our AD model following post-phenotypic changes such as increased Aβ accumulation and proliferation of microglial cells and astrocytes, which is consistent with anatomical studies reporting resilience of CR cells in post-mortem brains of AD patients (Fonseca et al., 1995). Using our key NAM molecule, α5-SOP002, we have demonstrated that abnormal synaptic inhibition received by CR interneurons in theAppNL-F/NL-F mouse model “normalized” to control levels. Moreover, paired whole-cell recordings revealed that α5-SOP002 had a pronounced effect at synapses between interneurons compared to synapses received by pyramidal cells, therefore impacting on dis-inhibition in the hippocampal CA1 region. This is important, given that we have previously demonstrated a gradual decline in the number of CCK- and SST-inhibitory interneurons in our AD model, suggesting an overall reduction in their inhibitory function, which was in stark contrast to the density of CR cells (Shi et al., 2019).
The sIPSPs recorded in this study are most likely due to the activation of synaptic α5 GABAARs, since we did not observe any significant change in either membrane potential or input resistance associated with the application of α5-SOP002 onto CR interneurons (or neither CCK nor pyramidal cells) . We suggest that in the CR interneuron network, showing zolpidem insensitivity, augmentation by diazepam and depression by α5−SOP002, the α5 subunit may coexist with another α5 subunit or either α2 or α3- subunit, where α5 pharmacology predominates.
However, interestingly, we observed a small positive (depolarisation) change in membrane potential in CR interneurons with α5-SOP002 in the AD model only, suggesting that these cells maybe in a state of excess tonic inhibition in the disease state. We suggest that the release from the abnormal tonic inhibition at CR cells, indicated by the depolarisation of the membrane potential, could be caused by negative allosteric modulation of extrasynaptic α5-receptors (Caraiscos et al., 2004; Magnin et al., 2019), which are tonically active due to increased levels of ambient GABA (Scimemi et al., 2005). Given that α5-SOP002 requires the presence of α− and γ−subunits, it is unlikely that it can affect the activity of other types of extrasynaptic GABAARs such as those containing the δ-subunit. However, the contribution of extrasynaptic α5 GABAARs to the CR interneuron network remains to be fully investigated.