For example, visual deprivation changes NMDAR function and alters the activity threshold, but not the capacity for LTD induction (Kirkwood et al., 1996 and Philpot et al., 2003). We tested this possibility by examining how neuromodulators affect the “voltage-dependence” of

pairing-induced synaptic plasticity over a wide range of pairing voltages (from −60mV to 0mV). In control conditions LTP and LTD can be selectively induced by pairing with voltage values above or below a crossover point that occurs at ∼−20mV (Figure 2A). Isoproterenol eliminated the induction of LTD and lowered the threshold voltage for induction of LTP. On the other hand, methoxamine eliminated LTP and extended the voltage range for LTD selleck chemical induction. These drugs also changed −20mV from being a membrane potential that is neutral under control conditions to one that induces LTP when Isoproterenol is present and LTD when methoxamine is present (Figure 2B). A two-way ANOVA test confirmed the significance of the effects of the drugs (F(6,150) = 4.627, p = 0.0002). These results indicate that the suppression of LTP and LTD by the adrenergic agonists does not result from a change in the induction threshold

because each agonist made it not just more difficult, but impossible to induce changes in one or the other polarity in the voltage range

we tested. Coactivation of α- and Doxorubicin β-adrenergic receptors restored bidirectional plasticity (Figure 1D), which indicates the suppressive effects mediated by one receptor type can be reversed or counterbalanced by activation of the other type. To determine whether the coactivation also affects the facilitating aspect of neuromodulation of plasticity (Seol et al., 2007), we examined the effects of coapplying 5 μM methoxamine and 10 μM isoproterenol on the “voltage-dependency” of pairing-induced plasticity. We found that pairing at voltages that normally yield little synaptic changes (−30mV and −10mV) result in robust LTD or LTP in the presence of both agonists (Figure 2C; two-way ANOVA: F(6,150) = 4.627, p = 0.0002). This increase in the slope of the voltage dependency PD184352 (CI-1040) of pairing induced plasticity indicates that the coactivation of α- and β-adrenergic receptors increases the gain of both LTP and LTD. Thus, the opposite individual effects of the α- and β-adrenergic receptors do not cancel out in a simple linear manner. Rather, the enhancement of one polarity of plasticity by a given adrenergic receptor is not affected by activation of the other receptor. Finally we examined whether other Gs- and Gq11-coupled receptors regulate plasticity in the same way as α- and β-adrenergic receptors.