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).