α5-SOP002 reduced inhibition, but exacerbated synaptic
hyperexcitability at CCK and principal cells
We then attempted to record from CCK and pyramidal cells in CA1. The
anatomically recovered interneurons resembled the most abundant sub-type
of CCK-expressing cells, the Schaffer collateral-associated (SCA)
interneuron with soma/dendrites and axons of these interneurons are
predominantly located in the SR and axonal branches predominantly
ramifying in SR (Ali, 2007). CCK and SST-expressing cells in aged AD
mice decline in densities during the pathogenesis of AD (Shi et al.,
2019), which hampered the yield of the recordings. Furthermore, we could
not record from SST-expressing cells in stratum oriens due to their
sparse appearance in the slices and the heavy myelination in this region
at 10-12 months of age.
The GABAAR α5 NAM, α5-SOP002, reduced the average sIPSP
amplitude and frequency of both CCK-SCA and pyramidal cells in
age-matched wild-type and APPNL-F/NL-F mice
(Figure 5, see Table 1 for detailed values). InAPPNL-F/NL-F mice, the average sIPSP frequency
and amplitude recorded at CCK-SCA cells reduced by 45.80 ± 10.40 % and
53.0 ± 7.5 %, of control values by bath- application of α5-SOP002,
(P < 0.05 for frequency and, P < 0.01
for amplitude, one-way ANOVA , with post-hoc Tukey’s test, n= 3,
Figure 5(A-B) and (E-F)). Similarly, inAppNL-F/NL-F mice sIPSP frequency and amplitude
recorded in pyramidal cells reduced following bath-application
α5-SOP002, by 16.50 ± 0.91 % (P > 0.05, n =5,
one-way ANOVA) and 49.17 ± 7.69% (P <0.001, n =5,
one-way ANOVA with post-hoc Tukey’s test) of control sIPSPs recorded in
age-matched wild-type mice, respectively (Figure 5 (D-E) and (G-H)).
However, in contrast, with bath-application of α5-SOP002, the sEPSP
properties recorded in CCK-SCA and pyramidal cells increased in
both wild-type and AppNL-F/NL-F mice (See Table
1). These cells recorded in the AD model displayed an abnormal level of
hyperexcitation and a deficit in inhibition compared to the healthy,
wild-type mice (Figure 5 (G-H)) (see also (Petrache et al., 2019; Shi et
al., 2019), which was further exacerbated when challenged with the
GABAAR α5 NAM, α5-SOP002. With bath application of
α5-SOP002, in the APPNL-F/NL-F mice, the
increase in sEPSP frequency and amplitude in CCK-SCA was, 42 ± 2.26 %
and 114 ± 9.04 % (P <0.05 (Frequency),P <0.01 (amplitude), n =3, one-way ANOVA), and in
pyramidal cells was, 32.48 ± 0.94 % and 48.0 ± 3.42 %
(P <0.01, n =5, one-way ANOVA),
respectively.