39-fold ± 0.06-fold). Although the increase in the excitatory PSP (EPSP) was still significant relative to the baseline SC response (p < 0.0001, n = 46), the magnitude of ITDP was significantly reduced by GABA receptor (GABAR) blockade (p < 0.0001, unpaired t test) (Figures 1B and 1D). These results

confirm the importance of inhibition for ITDP (Xu et al., 2012; EPZ-6438 chemical structure but cf. Dudman et al., 2007; see Discussion) but do not distinguish whether it is required for ITDP induction or expression. To address this point, we blocked inhibition only during ITDP induction (Figure 1C). First, we measured PP and SC PSPs with inhibition intact and then rapidly applied GABAR antagonists (4 μM SR, 2 μM CGP). As removal of inhibition increased the magnitude of the PSPs, we adjusted the stimulation strength of the two pathways to match the initial PSP Panobinostat cell line amplitude and then delivered the ITDP induction protocol. Next, we washed out the antagonists using a fast perfusion system to restore inhibition within 5 min after pairing and we reset the stimulation strengths to their initial values. In this paradigm, the pairing protocol produced a large potentiation of the SC PSP (2.78-fold ±

0.19-fold change; p < 0.0001, n = 16), similar to the size of ITDP with inhibition intact (p = 0.2125, PD184352 (CI-1040) unpaired t test) (Figures 1C and 1D). This implies that inhibition is required for the full expression but not induction of ITDP. The decrease in ITDP with GABAR blockade suggests that the increase in the SC-evoked PSP during ITDP results, at least in part, from a long-lasting decrease in FFI. To test this idea, we measured the PP- and SC-evoked inhibitory postsynaptic currents (IPSCs) before and after ITDP induction by voltage clamping the soma membrane at +10 mV, near the EPSC reversal potential (Figures 2A1–2A4). Stimulation of the PP or SC inputs evoked a large outward IPSC in the CA1 PN soma that was fully blocked by GABAR antagonists (data

not shown, but see Figure 6D1). Glutamate receptor blockers also reduced the IPSC to <5% of its initial value, indicating that the IPSC results from feedforward excitation of local INs, rather than direct activation of inhibitory axons (Figures S1A–S1C available online). The SC-evoked IPSC was strongly reduced following induction of ITDP (under current clamp) by 58.8% ± 3.7% (from 1.01 ± 0.09 nA to 0.42 ± 0.06 nA; p < 0.0001, paired t test, n = 9) (Figures 2A1–2A4), whereas the PP IPSC was unchanged (0.24 ± 0.03 nA before versus 0.25 ± 0.2 nA after ITDP; p = 0.4034, paired t test, n = 9). This supports the view that the expression of ITDP involves a reduction in FFI activated specifically by the SC inputs.