Application of GABAAR and GABABR blockers to PSEM-treated slices produced only an ∼12% further increase in the SC-evoked PSP (to 9.77 ± 1.01 mV, p < 0.01, n = 6; Figure 6E1). Thus, CCK IN silencing blocks almost all SC-evoked FFI. Furthermore,

we found that CCK INs also make a dominant contribution to the FFI in CA1 PNs evoked by PP stimulation (Figure S4). Selective silencing of PSAM+ CCK INs with PSEM application produced an 80% reduction in the amplitude of the PP-evoked somatic IPSC (p < 0.0005, n = 5) and a corresponding increase Autophagy inhibitor in the PP-evoked PSP (p < 0.0001, two-way ANOVA with Sidak’s multiple comparison test, n = 5). These silencing experiments demonstrate that the CCK INs are responsible for the majority of FFI that controls synaptic responses of CA1 PNs elicited by both the SC and PP inputs. The findings that CCK IN silencing robustly increased the PSP amplitude (by ∼100%) and occluded any further increase in the PSP upon subsequent GABAR blockade resemble the effects seen upon induction of ITDP (Figure 2). Such results support the view that selective silencing of CCK INs produces a large reduction in inhibition capable of accounting for the magnitude

of iLTD observed during ITDP. To determine whether the CCK INs are indeed required for expression of Gefitinib datasheet iLTD during ITDP, we examined the effects of PSEM-mediated silencing on the magnitude of ITDP. PSEM ligand was applied (at 3 μM) to hippocampal slices either from CCK-ires-Cre mice injected with rAAV that expressed PSAM in a Cre-dependent manner (CCK-Cre-PSAM) or from uninjected control littermates (CCK-Cre). When the control slices were exposed to PSEM, the pairing protocol elicited a normal-sized ITDP (2.9-fold ± 0.26-fold) ( Figures 1C and 2A1–2A4). In contrast, there was a strong suppression of ITDP when the pairing protocol was applied to PSAM-expressing slices exposed to PSEM (p < 0.0002, unpaired t test; CCK-Cre PSAM group, n = 7; CCK-Cre group, n = 6). With CCK INs silenced, the pairing protocol produced only a 1.42-fold ± Oxymatrine 0.09-fold

increase in the SC-evoked PSP, similar to the magnitude of ITDP during GABAR blockade ( Figure 1C). Silencing of CCK INs also significantly reduced the extent of iLTD of the IPSC during ITDP. Thus, PSAM-expressing slices exposed to PSEM displayed only an 8.3% ± 1.7% decrease in the SC-evoked IPSC following induction of ITDP compared to the 60.5% ± 3.2% decrease in the IPSC seen with control slices (p < 0.0001; Figures 7B1–7B3). Application of GABAR antagonists 30–40 min after ITDP induction caused only a small increase (∼15%) in the SC PSP in both groups (p = 0.7273, one-way ANOVA; Figure 7A3), indicating a similar extent of loss of inhibition. These findings support the hypothesis that iLTD during ITDP results from a selective depression of FFI mediated by CCK INs.