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1 Adrenergic Receptors
* To whom correspondence should be addressed. E-mail: mcmahon{at}physiology.uab.edu.
Neurons located in the locus coeruleus project to hippocampus and provide noradrenergic innervation necessary for hippocampal-dependent learning and memory. The mechanisms underlying the function of norepinephrine (NE) in memory processing are unknown but likely reside in the ability of NE to modulate the efficacy of glutamate synaptic transmission via activation of G-protein coupled adrenergic receptors. Here we show that application of NE to rat hippocampal slices in vitro induces a long-term depression (LTD) of synaptic transmission at excitatory CA3-CA1 synapses that persists for at least 40 minutes following agonist washout. This LTD, which we refer to as NE LTD, is mediated by activation of 
1 adrenergic receptors since the 1 agonist methoxamine can induce LTD at the same magnitude as that induced with the non-selective adrenergic agonist NE. Furthermore, NE LTD induced by either NE or methoxamine is blocked with the 1 receptor antagonist, prazosin, but is unaffected by antagonists of 1 and 
receptors. This plasticity persists in the presence of the GABAA receptor antagonist bicuculline indicating that adrenergic modulation of GABAA receptor-mediated transmission does not underlie NE LTD. Induction of NE LTD requires presynaptic activity during agonist application and postsynaptic activation of N-methyl-D-aspartate receptors (NMDARs), fulfilling Hebbian criteria of coincident pre- and post-synaptic activity. The expression of NE LTD is likely to be postsynaptic since paired-pulse facilitation ratios during NE LTD expression are not different from baseline, similar to LTD induced by low frequency stimulation. Thus we report the identification and characterization of a novel Hebbian form of LTD in hippocampus that is induced following activation of 1 adrenergic receptors. This plasticity may be a mechanism by which the adrenergic system participates in normal cognitive function.
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