Inhibition recorded from spontaneous synaptic events
The effect of α5-SOP002 at inhibitory CR interneurons was determined on brain slices by performing whole-cell recordings under current clamp mode. Spontaneous inhibitory postsynaptic potentials (sIPSPs) and spontaneous excitatory postsynaptic potentials (sEPSPs) were recorded from CR interneurons at 10-12 months old wild-type andAppNL-F/NL-F  mice at holding membrane potentials of -60mV (to observe both excitation and inhibition, Figure 4 (A-D)), the average data are shown in Table 1. The average peak frequency and amplitude of sIPSPs significantly increased in the AD model compared to wild-type age-matched mice at -60 mV, was consistent with our previous publication that reported this interesting abnormal observation in the CR cells (Shi et al., 2019). In theAppNL-F/NL-F  mice sIPSP frequency and amplitude was abnormally higher by 93.4 ± 7.5 % (P <0.01,n =5, unpaired, two-tailed Student’s t-test) and 55.6 ± 23.3 % (P <0.01, n =5, unpaired, two-tailed Student’s t-test) of control sIPSPs recorded in age-matched wild-type mice, respectively (Figure 4 (C)).
Bath-application of α5-SOP002 (1 µM) reduced the sIPSP frequency and amplitude in both wild-type and AppNL-F/NL-Fmice (see Table 1 for details). The significantly reduced sIPSP frequency (48 ± 3.2 %, P <0.01, n =5, one-way ANOVA with post-hoc Bonferroni’s test) and amplitude (56.3 ± 5.7 %,P <0.01, n =5, one-way ANOVA with post-hoc Bonferroni’s test) recorded in CR cells fromAppNL-F/NL-F  mice was comparable to the control CR cells recorded in age-matched wild-type mice. The average sEPSP frequency and amplitude also changed, but the slight increase was not significantly different from control mean (Figure 4 (D), Table 1).
Interestingly, in the AppNL-F/NL-F mice, bath-application of α5-SOP002 also caused an average ~5 mV depolarisation of the cell membrane, suggesting a reduction in tonic inhibition.