For the initial set of experiments we used extracellular recording in acutely prepared rat hippocampal slices and stimulated Docetaxel datasheet two independent inputs onto the same population of neurons. We decided to test the effects of the JAK inhibitor AG490 (10 μM), since this inhibitor has been shown to interfere with learning and memory (Chiba et al., 2009b). We found that AG490 had no effect on baseline transmission (100% ± 1% before and 101% ± 1% during AG490 application, n = 13). Next we tested the effects

of AG490 on NMDAR-LTP, since this is the most widely studied cellular correlate of learning and memory (Bliss and Collingridge, 1993). However, we found no difference between the level of LTP induced in the control

input, in which AG490 was applied immediately after the tetanus, or in the input tetanized in the presence of AG490 (Figure 1A). Thus, the level of LTP obtained 30 min following the tetanus, expressed as a percentage of baseline, was 135% ± 4% and 145% ± 3% (n = 4), respectively. These values were similar to the level of LTP induced in untreated inputs (140% ± 3% of baseline, n = 6; Figure 1C). Since more recent evidence has suggested that NMDAR-LTD is also involved in some forms of learning and memory (see Collingridge et al., 2010) we next tested AG490 on this form of synaptic plasticity. In all experiments, AG490 completely prevented the induction of NMDAR-LTD induced by low-frequency stimulation (LFS; Compound Library research buy comprising of 900 stimuli delivered at 1 Hz), though usually a short-term depression remained (Figure 1B). In all cases, the block of NMDAR-LTD was fully reversible since a second, identical period of LFS induced LTD that was similar to that observed under control conditions. Thus, 60 min following the first LFS, delivered in presence of AG490, the responses were 99% ± 4% of baseline and 60 min following the second LFS, delivered after washout of AG490, they were 74% ± 11% of baseline (n = 6). In contrast to the dramatic effect on the induction of NMDAR-LTD, AG490 had no effect on the expression phase of this process. Parvulin Thus, LFS induced an LTD that was 71% ± 9% and 72% ± 9% of

baseline (n = 6), before and following the application of AG490, respectively. Since these experiments were all performed using two inputs, the ability of AG490 to selectively and reversibly block the induction of NMDAR-LTD without affecting baseline transmission or the expression of NMDAR-LTD were all internally controlled. Next, we explored whether the effects of AG490 were specific for de novo NMDAR-LTD or whether it blocked all forms of LTD. To do this we investigated depotentiation, the reversal of a previously potentiated input. For these experiments we compared, in the two inputs, the level of depotentiation before the application and in the presence of AG490. Under both sets of conditions, LFS reversed LTP to baseline conditions (Figure 1C).