Alpha1-Adrenergic Receptor Mediated Long-Term Depression at CA3-CA1 Synapses Can be Induced via Accumulation of Endogenous Norepinephrine and is Preserved Following Noradrenergic Denervation

Dyer-Reaves, K.; Goodman, A. M.; Nelson, A. R.; McMahon, L. L.

doi:10.1101/648873

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bioRxiv · 10.1101/648873

Alpha1-Adrenergic Receptor Mediated Long-Term Depression at CA3-CA1 Synapses Can be Induced via Accumulation of Endogenous Norepinephrine and is Preserved Following Noradrenergic Denervation

Dyer-Reaves, K.·Goodman, A. M.·Nelson, A. R.·McMahon, L. L.

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Abstract

Locus coeruleus (LC) provides the sole source of noradrenergic (NA) innervation to hippocampus, and it undergoes significant degeneration early in Alzheimers 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 1 adrenergic receptors (1ARs) induces long-term depression (LTD) at CA3-CA1 synapses. Here we investigated whether accumulation of endogenous NE via pharmacological blockade of NE transporters (NET) and the NE degradative enzyme, monoamine oxidase (MAO), can induce 1AR LTD, as these inhibitors are used clinically. Further, we sought to determine how degeneration of hippocampal NA innervation, as occurs in AD, impacts 1AR function and 1AR LTD. Bath application of NET and MAO inhibitors in slices from control rats reliably induced 1AR LTD when {beta} 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, 1AR LTD was successfully induced using either the 1AR 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 1AR LTD remain functional. Furthermore, we posit that 1AR activation could be a viable therapeutic target for pharmacological intervention in AD and other diseases involving malfunctions of NA neurotransmission.

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Dyer-Reaves, K., Goodman, A. M., Nelson, A. R., McMahon, L. L.. 2019-05-30. Alpha1-Adrenergic Receptor Mediated Long-Term Depression at CA3-CA1 Synapses Can be Induced via Accumulation of Endogenous Norepinephrine and is Preserved Following Noradrenergic Denervation. https://doi.org/10.1101/648873

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