In a similar fashion, we found CHIR-99021 purchase that the magnitude and duration of the suppression of LTP by methoxamine (5 μM) depends on the duration of the agonist exposure (two-way ANOVA: F(1,24) = 25.2, p < 0.0001) (Figure 6G) and it was reversed within 2 hr (CTR: 150.1% ± 4.1%, n = 4; MTX: 142.4% ± 4.2%, n = 11; p = 0.20) (Figure 6G). Altogether, these results indicate that the selective adrenergic suppression of LTP and LTD is not restricted to synapses in

visual cortical layer II/III. The neuromodulation of LTP and LTD is an attractive mechanism to subordinate the magnitude and polarity of plasticity to behavioral demands. To examine whether neuromodulation of plasticity is operational in vivo we exploited the fact that α1 adrenergic agonists bring synapses into an “LTD-only” state, whereas β agonists produce an “LTP-only” state (see Figure 2). We reasoned that systemic application of α1 or β agonists in conjunction with visual stimulation to drive activity in V1 should respectively depress or potentiate active synapses in the visual cortex. Thus, anesthetized rats were first injected with α1 or β agonists or vehicle (intraperitoneally [i.p.], 15 mg/kg) and subjected to 1 hr of strong monocular visual stimulation to drive activity in V1 (see Experimental Procedures) (Girman et al., 1999).

Then, the changes in synaptic strength were evaluated ex vivo by quantifying miniature EPSCs (mEPSCs) recorded from layer 2/3 pyramidal neurons located in the monocular segment of V1, either contralateral or ipsilateral to the stimulated eye (see Figures 7A and 7B). The effects of the pretreatment with α1 agonist methoxamine and monocular EPZ-6438 concentration stimulation are shown in Figure 7C. On average, mEPSCs recorded in the contralateral (stimulated)

V1 were smaller in amplitude than the mEPSCs recorded in the ipsilateral (nonstimulated) cortex (Contra: 9.13 ± 0.07 pA, n = 22 cells; Ipsi: 11.37 ± 0.06 pA, n = 25 cells, seven rats; p < 0.0001) (Figure 7C). The distribution of mEPSC amplitude distributions were significantly different (Wilcoxon test: p < 0.0001) in a multiplicative manner, that is, the distribution of all contralateral mEPSCs is similar to the distribution of all ipsilateral mEPSCs scaled down by a factor of 0.8032 (Wilcoxon test: p = 0.9151). These results are consistent with a scenario in which the stimulation much activated most of the synapses and that methoxamine promoted the induction of LTD in these active synapses. Changes in the opposite direction were observed after pretreatment with the β agonist isoproterenol. The mEPSCs were larger in the contralateral, stimulated, V1 (Contra = 12.49 ± 0.10 pA, n = 15 cells; Ipsi = 10.55 ± 0.09 pA, n = 16 cells, six rats; p < 0.0001) (Figure 7D), and these differences were consistently observed across individuals (paired test: p = 0.007) (Figure 7D). On the other hand, the differences in the mEPSC amplitude distributions were significant (Wilcoxon test: p = 0.