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.