Our results complement and extend the findings of previous studies learn more on hippocampal ITDP (Dudman et al., 2007 and Xu et al., 2012). Similar to previous results, induction of both ITDP and iLTD are sharply tuned to the −20 ms pairing interval (Dudman et al., 2007), require activation of NMDA and mGluR1a receptors and Ca2+-dependent signaling (Dudman et al., 2007 and Xu et al., 2012), and involve eCB retrograde messengers (Xu et al., 2012, but see below). However, in contrast to previous conclusions that

hippocampal ITDP is mediated solely by long-term changes in excitation (Dudman et al., 2007 and Xu et al., 2012), the core finding of our study is that the major mechanism contributing to the enhanced synaptic depolarization during ITDP results from iLTD. Although Xu et al., (2012) did find that ITDP was suppressed by GABAR antagonists and required eCB signaling, the targets of eCB action were not identified and their study concluded that ITDP does not alter synaptic inhibition. This latter conclusion was based on the authors’ finding that the ITDP pairing protocol had no effect on IPSCs evoked by direct stimulation

of GABAergic axons (see Figure 2D of Xu Selleckchem Tyrosine Kinase Inhibitor Library et al., 2012). However, this result is confounded by the fact that direct inhibition was measured in the continuous presence of AMPAR and NMDAR antagonists, which will prevent the postsynaptic depolarization and NMDAR-mediated Ca2+ influx necessary to induce both eLTP (Dudman et al., 2007) and iLTD (see Figures 9 and S6). Unlike the results of Xu et al. (2012) and our present study, an earlier study from our laboratory reported that the magnitude of ITDP was not altered by the continuous see more blockade of GABARs (Dudman et al., 2007). Although we cannot fully explain the discrepancy between our present results and this previous study, the standard errors in the earlier data with GABAR antagonists were quite large owing

to a small number of experiments and large experimental variability, which may have obscured the change in the magnitude of ITDP. A number of studies indicate that CCK INs mediate relatively slow, long-lasting inhibition, compared to the more rapid inhibition mediated by PV INs (Daw et al., 2009, Glickfeld and Scanziani, 2006 and Hefft and Jonas, 2005). The slow CCK IN-mediated IPSP results, in part, from an asynchronous component of GABA release and the slower postsynaptic current mediated by α2 subunit-containing GABAARs (Freund and Katona, 2007). This has led to the idea that the CCK INs are best suited for regulating sustained activation of principle neurons, rather than for regulating fast depolarization elicited by excitatory synaptic input. However, we found that optogenetic activation of the CCK IN population produces a prominent fast IPSC that is even larger than that elicited by PV IN stimulation.