Preservation of α5 GABAARs in CA1 in the aged mouse model of AD
We show for the first time, that the α5 GABAARs in the CA1 region of the hippocampus are expressed on CR- expressing interneurons, specialised for dis-inhibition, but also SST- and CCK- expressing interneurons, specialised for fine-tuning pyramidal cell activity. The rationale for selecting CCK- and SST- expressing cells in our experiments stems from previous studies showing that dendrite-targeting interneurons form synapses with the pyramidal cells that incorporate the α5 subunit-containing GABAARs (Ali et al., 2008). However, in the current study, we show that SST- and CCK- expressing cells are also recipients of postsynaptic inhibition mediated by α5 GABAARs.
Our findings corroborate previous studies that have demonstrated that α5 GABAARs are preserved in post-mortem tissue obtained from AD patients (Howell et al., 2000), but also studies showing expression of α5 GABAARs in pyramidal cells (Brunig et al., 2002). Our experiments demonstrate expression of these receptors on the soma of CR, SST and CCK interneurons in addition to pyramidal cells. Since SST and CCK cells decline in disease (Shi et al., 2019), this distribution could be due to a subgroup of SST interneurons compensating for the reduction in numbers by upregulating α5 GABAAR expression. Given that both CCK and SST cells are hyperactive in AD (Shi et al., 2019; Zhang et al., 2016), it is possible that α5 expression represents a compensatory mechanism.
Investigation into the levels of α5 expression on dendrites showed larger variability, notable being the level of expression on SST interneurons in the AppNL-F/NL-F mice, which could be linked to the differential input those cells receive. Similarly, pyramidal cells showed larger variability, and we propose that this is input-dependent. Earlier studies investigating regulation of GABAAR surface expression show that, during seizures, receptors can be rapidly internalised leading to increased neuronal activity (Goodkin et al., 2007). A similar mechanism could be taking place in AD, contributing to the abnormal inhibitory-excitatory balance that characterises this disease (Petrache et al., 2019).