NORADRENERGIC REGULATION OF SYNAPTIC PLASTICITY IN THE HIPPOCAMPAL CA1 REGION

The effects of norepinephrine (NE) and related agents on long-lasting changes in synaptic efficacy induced by several patterns of afferent s timuli were investigated in the CA1 region of rat hippocampal slices. NE (10 mu M) showed little effect on the induction of long-term potent iation (LTP) triggered by theta-burst-patterned stimulation, whereas i t inhibited the induction of long-term depression (LTD) triggered by 9 00 pulses of 1-Hz stimulation. In nontreated slices, 900 pulses of sti muli induced LTD when applied at lower frequencies (1-3 Hz), and induc ed LTP when applied at a higher frequency (30 Hz). NE (10 mu M) caused a shift of the frequency-response relationship in the direction prefe rring potentiation. The effect of NE was most prominent at a stimulus frequency of 10 Hz, which induced no changes in control slices but cle arly induced LTP in the presence of NE. The facilitating effect of NE on the induction of LTP by 10-Hz stimulation was blocked by the beta-a drenergic receptor antagonist timolol (50 mu M), but not by the alpha receptor antagonist phentolamine (50 mu M), and was mimicked by the be ta-agonist isoproterenol (0.3 mu M), but not by the alpha(1) agonist p henylephrine (10 mu M). The induction of LTD by 1-Hz stimulation was p revented by isoproterenol but not by phenylephrine, indicating that th e activation of beta-receptors is responsible for these effects of NE. NE (10 mu M) also prevented the reversal of LTP (depotentiation) by 9 00 pulses of 1-Hz stimulation delivered 30 min after LTP induction. In contrast to effects on naive (nonpotentiated) synapses, the effect of NE on previously potentiated synapses was only partially mimicked by isoproterenol, but fully mimicked by coapplication of phenylephrine an d isoproterenol. In addition, the effect of NE was attenuated either b y phentolamine or by timolol, indicating that activation of both alpha (1) and beta-receptors is required. These results show that NE plays a modulatory role in the induction of hippocampal synaptic plasticity. Although beta-receptor activation is essential, alpha(1) receptor acti vation is also necessary in determining effects on previously potentia ted synapses.