Alpha1-Adrenergic Receptor Mediated Long-Term Depression at CA3-CA1 Synapses Can Be Induced Accumulation of Endogenous Norepinephrine and Is Preserved Following Noradrenergic Denervation.

Locus coeruleus (LC) provides the sole source of noradrenergic (NA) innervation to hippocampus, and it undergoes significant degeneration early in Alzheimer's disease (AD). Norepinephrine (NE) modulates synaptic transmission and plasticity at hippocampal synapses which likely contributes to hippocampus-dependent learning and memory. We previously reported that pharmacological activation of α adrenergic receptors (αARs) induces long-term depression (LTD) at CA3-CA1 synapses. Here, we investigated whether accumulation of endogenous NE pharmacological blockade of norepinephrine transporters (NETs) and the NE degradative enzyme, monoamine oxidase (MAO), can induce αAR LTD, as these inhibitors are used clinically. Further, we sought to determine how degeneration of hippocampal NA innervation, as occurs in AD, impacts αAR function and αAR LTD. Bath application of NET and MAO inhibitors in slices from control rats reliably induced αAR LTD when β adrenergic receptors were inhibited. To induce degeneration of LC-NA innervation, rats were treated with the specific NA neurotoxin DSP-4 and recordings performed 1-3 weeks later when NA axon degeneration had stabilized. Even with 85% loss of hippocampal NA innervation, αAR LTD was successfully induced using either the αAR agonist phenylephrine or the combined NET and MAO inhibitors, and importantly, the LTD magnitude was not different from saline-treated control. These data suggest that despite significant decreases in NA input to hippocampus, the mechanisms necessary for the induction of αAR LTD remain functional. Furthermore, we posit that αAR activation could be a viable therapeutic target for pharmacological intervention in AD and other diseases involving malfunctions of NA neurotransmission.