The objective of this study was to evaluate the role of ␤-adrenergic receptors in modulating associative long-term potentiation (LTP) induced at CA1 synapses. Two independent Schaffer collateral pathways were stimulated in hippocampal slices. The field EPSP (fEPSP) response evoked in one pathway (the weak pathway) was small, whereas a large response, usually 80 -90% of the maximum, was evoked in the strong pathway. After recording of the baseline fEPSP evoked at 0.033 Hz, LTP of the weak pathway could be associatively induced by paired stimulation of the weak and strong pathways 100 times at 6 sec intervals, with stimulation of the weak pathway preceded 3-10 msec. However, pairing protocols with an interval between stimulation of the two pathways Ͼ10 msec resulted in no LTP. The induced LTP was NMDA receptor dependent, because 50 M D,L-APV blocked its induction. Bath application of 1 M isoproterenol enhanced LTP by increasing the window of the stimulation interval up to 15 msec but did not affect the magnitude of the LTP induced by pairing protocols with intervals Ͻ10 msec. Similar results were obtained when the experiments were repeated using whole-cell recording. These results suggest that activation of ␤-adrenergic receptors can enhance associative LTP by increasing the width of the time window rather than the magnitude of the LTP. Enhancement of LTP by ␤-adrenergic receptors was blocked in slices by pretreatment with inhibitors of protein kinase A or mitogen-activated protein kinase, suggesting that these signaling cascades are involved in this process.

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Iron-induced oxidative injuries in locus coeruleus (LC), a major source of noradrenergic projections in the central nervous system (CNS), were investigated in chloral-hydrate anesthetized rats. Local infusion of iron dose-dependently elevated lipid peroxidation of iron-infused LC seven days after infusion. At the same time, norepinephrine content in the hippocampus ipsilateral to the iron-infused LC was decreased in a concentration-dependent manner. Our immunostaining study demonstrated reduced tyrosine hydroxylase-positive neurons in the iron-infused LC, indicating a reduction of neuron number by iron infusion. The involvement of apoptosis in iron-induced oxidative injuries was studied. An abrupt increase in cytosolic cytochrome c content was demonstrated in the infused LC 48 hours after iron infusion. TUNEL-positive cells, an indication of apoptosis, were detected in the iron-infused LC. In an attempt to prevent iron-induced neurotoxicity, vitamin D3, an active metabolite of vitamin D, was systemically administered. Iron-induced increases in cytosolic cytochrome c and TUNEL-positive cells were reduced by this treatment. Furthermore, systemic administration of vitamin D3 attenuated iron-induced oxidative injuries in the infused LC. Our data suggest that local infusion of iron in LC induced oxidative stress and resulted in programmed cell death in the LC-hippocampal noradrenergic system. Furthermore, vitamin D3 may be neuroprotective and therapeutic in attenuating iron-induced neurotoxicity in CNS.

We examined the mechanisms underlying spike-timing-dependent plasticity induction at resting and conditioned lateral perforant pathway (LPP) synapses in the rat dentate gyrus. Two stimulating electrodes were placed in the outer third of the molecular layer and in the granule cell layer in hippocampal slices to evoke field excitatory postsynaptic potentials (fEPSPs) and antidromic field somatic spikes (afSSs), respectively. Long-term potentiation (LTP) of LPP synapses was induced by paired stimulation with fEPSP preceding afSS. Reversal of the temporal order of fEPSP and afSS stimulation resulted in long-term depression (LTD). Induction of LTP or LTD was blocked by D,L-2-amino-5-phosphonopentanoic acid (AP5), showing that both effects were N-methyl-D-aspartate receptor (NMDAR)-dependent. Induction of LTP was also blocked by inhibitors of calcium-calmodulin kinase II, protein kinase C or mitogen-activated/extracellular-signal regulated kinase, suggesting that these are downstream effectors of NMDAR activation, whereas induction of LTD was blocked by inhibitors of protein kinase C and protein phosphatase 2B. At LPP synapses previously potentiated by high-frequency stimulation or depressed by low-frequency stimulation, paired fEPSP-afSS stimulation resulted in 'de-depression' at depressed LPP synapses but had no effect on potentiated synapses, whereas reversal of the temporal order of fEPSP-afSS stimulation resulted in 'de-potentiation' at potentiated synapses but had no effect on depressed synapses. Induction of de-depression and de-potentiation was unaffected by ap5 but was blocked by 2-methyl-6-(phenylethynyl) pyridine hydrochloride, a group I metabotropic glutamate receptor blocker, showing that both were NMDAR-independent but group I metabotropic glutamate receptor-dependent. In conclusion, our results show that spike-timing-dependent plasticity can occur at both resting and conditioned LPP synapses, its induction in the former case being NMDAR-dependent and, in the latter, group I metabotropic glutamate receptor-dependent.

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