Abstract
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 α1 adrenergic receptors (α1ARs) induces long-term depression (LTD) at CA3-CA1 synapses. Here, we investigated whether accumulation of endogenous NE via pharmacological blockade of norepinephrine transporters (NETs) and the NE degradative enzyme, monoamine oxidase (MAO), can induce α1AR LTD, as these inhibitors are used clinically. Further, we sought to determine how degeneration of hippocampal NA innervation, as occurs in AD, impacts α1AR function and α1AR LTD. Bath application of NET and MAO inhibitors in slices from control rats reliably induced α1AR 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, α1AR LTD was successfully induced using either the α1AR 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 α1AR LTD remain functional. Furthermore, we posit that α1AR activation could be a viable therapeutic target for pharmacological intervention in AD and other diseases involving malfunctions of NA neurotransmission.
Highlights
Noradrenergic (NA) input from the locus coeruleus (LC) to hippocampus is critical for hippocampus-dependent learning and memory (Koob et al, 1978; Harro et al, 1999; Lemon et al, 2009; Gibbs et al, 2010), and its degeneration in Alzheimer’s disease (AD) has been well documented (Forno, 1966; Yamada and Mehraein, 1977; Zarow et al, 2003)
We found that no additional long-term depression (LTD) could be induced by Phe in the presence of CAP, such that α1 adrenergic receptors (α1ARs) LTD induced by CAP that was not significantly different when Phe was added to the CAP mixture (denoted CAPP; Figure 5, CAP: n = 6; CAPP: n = 10, t(6) = 2.08 p = 0.0827)
We show that pharmacological inhibition of norepinephrine transporter (NET) and monoamine oxidase (MAO) leads to extracellular accumulation of NE which is capable of activating adrenergic receptor (AR) that modulate synaptic efficacy at CA3-CA1 synapses
Summary
Noradrenergic (NA) input from the locus coeruleus (LC) to hippocampus is critical for hippocampus-dependent learning and memory (Koob et al, 1978; Harro et al, 1999; Lemon et al, 2009; Gibbs et al, 2010), and its degeneration in Alzheimer’s disease (AD) has been well documented (Forno, 1966; Yamada and Mehraein, 1977; Zarow et al, 2003). Given that activation of α1ARs using exogenous agonists induces LTD at hippocampal CA3-CA1 synapses (Scheiderer et al, 2004, 2008), we wanted to determine if increasing endogenous extracellular NE accumulation via pharmacological inhibition of the norepinephrine transporter (NET) and the degradative enzyme monoamine oxidase (MAO) induces α1AR LTD This is important since these inhibitors are widely used as therapeutic treatments in disorders such as ADHD and depression, where imbalances in catecholamine neurotransmission, NE, are known to occur (Zametkin and Rapoport, 1987; Castellanos et al, 1996; Vanicek et al, 2014; Israel, 2015). Because LC degeneration, and loss of hippocampal NA innervation, is clinically relevant to normal aging, AD, and Parkinson’s disease (PD; Mann, 1983; Mann et al, 1983; Marien et al, 2004; Szot, 2012), we set out to investigate the impact of NA degeneration on the ability of pharmacological activation of α1ARs to induce LTD at hippocampal CA3-CA1 synapses
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