183 (Wilcoxon test: p = 0.782). In control rats injected with vehicle the average mEPSC amplitude was similar in the contra and ipsilateral NVP-BKM120 chemical structure cortices (Contra: 11.10 ± 0.10 pA, n = 11 cells; Ipsi: 10.94 ± 0.08 pA, n = 16 cells, five rats; Wilcoxon test: p = 0.2375) (Figure 7E) in all animals tested (p = 0.73) (Figure 7E) indicating that visual stimulation

per se, does not produce plastic changes in mEPSC amplitude. The distribution of mEPSCs in the ipsilateral (nonstimulated) cortex was similar to the distribution of the contralateral mEPSCs (Wilcoxon test: p = 0.4298) (Figure 7E), and also similar to the distribution of ipsilateral mEPSCs from rats treated with methoxamine or isoproterenol, supporting the idea that neuromodulators promote changes in activated synapses only. Finally, we examined the role of NMDA receptors and tested the effects of systemic injection of the competitive antagonist CPP (15 mg/kg UMI-77 clinical trial i.p 20 min prior monocular stimulation), a dose that blocks experience-dependent plasticity without affect visual responses (Frenkel et al., 2006 and Sato

and Stryker, 2008). The CPP injections consistently abolished the differences in mEPSC amplitude between the contra- and ipsilateral cortices in rats treated with methoxamine (n = 5; Wilcoxon test: p = 0.8489) or isoproterenol (n = 5; Wilcoxon test: p = 0.9686) (Figure 7F), which is consistent with a role of NMDAR in the visually induced plasticity promoted by neuromodulators. A two-way ANOVA test confirmed the significance of the differences in mEPSC amplitude across treatments (F(9,196) = 10.4139, p < 0.001) (Figure 7G). The frequency of the mEPSCs, on the other hand, was not affected (two-way unless ANOVA, F(9,196) = 0.9163, p = 0.512) (Figure 7H). Altogether the results indicate that activation of α and β adrenoreceptors can be used to globally

potentiate and depress synapses in a controlled manner. The results described above (Figure 7) suggest that monocular stimulation induced LTD throughout the contralateral cortex when delivered in conjunction with methoxamine, and induced LTP when delivered with isoproterenol. To further examine this idea we tested whether the treatment with neuromodulators and monocular stimulation, as it induced plasticity in vivo, occludes subsequent pairing-induced LTD or LTP in vitro. In control rats (stimulated but injected with vehicle, n = 5 rats) (Figure 8B) both hemispheres expressed comparable magnitude of LTP (p = 0.23) and LTD (p = 0.56). In stimulated rats injected with methoxamine (n = 7 rats) (Figure 8C) LTD was robust in the ipsilateral hemisphere (nonstimulated cortex) but absent in the contralateral one (p < 0.0001), consistent with the idea that LTD was already induced in these synapses. Interestingly, pairing at 0mV potentiated synapses in the contralateral, but not in the ipsilateral, hemisphere (p < 0.0001).