Noradrenaline Release from Locus Coeruleus Terminals in the Hippocampus Enhances Excitation-Spike Coupling in CA1 Pyramidal Neurons Via β-Adrenoceptors

Abstract

<jats:title>Abstract</jats:title> <jats:p>Release of the neuromodulator noradrenaline signals salience during wakefulness, flagging novel or important experiences to reconfigure information processing and memory representations in the hippocampus. Noradrenaline is therefore expected to enhance hippocampal responses to synaptic input; however, noradrenergic agonists have been found to have mixed and sometimes contradictory effects on Schaffer collateral synapses and the resulting CA1 output. Here, we examine the effects of endogenous, optogenetically driven noradrenaline release on synaptic transmission and spike output in mouse hippocampal CA1 pyramidal neurons. We show that endogenous noradrenaline release enhances the probability of CA1 pyramidal neuron spiking without altering feedforward excitatory or inhibitory synaptic inputs in the Schaffer collateral pathway. β-adrenoceptors mediate this enhancement of excitation-spike coupling by reducing the charge required to initiate action potentials, consistent with noradrenergic modulation of voltage-gated potassium channels. Furthermore, we find the likely effective concentration of endogenously released noradrenaline is sub-micromolar. Surprisingly, although comparable concentrations of exogenous noradrenaline cause robust depression of slow afterhyperpolarization currents, endogenous release of noradrenaline does not, indicating that endogenous noradrenaline release is targeted to specific cellular locations. These findings provide a mechanism by which targeted endogenous release of noradrenaline can enhance information transfer in the hippocampus in response to salient events.</jats:p>

Peripheral CB1 receptor blockade acts as a memory enhancer through an adrenergic-dependent mechanism

“…Although norepinephrine can bind to both α-or β-adrenergic receptors, synaptic information and plasticity in the hippocampus would depend largely on the activation of β-adrenergic receptors (A. Kemp & Manahan-Vaughan, 2008 (Bacon et al, 2020) and improves memory through a βadrenergic-dependent mechanism (Hagena et al, 2016;N. Hansen & Manahan-Vaughan, 2015).…”

“…Although norepinephrine can bind to both α-and β-adrenergic receptors, synaptic information and plasticity in the hippocampus is proposed to depend largely on the activation of βadrenergic receptors (Kemp & Manahan-Vaughan, 2008). Indeed, LC stimulation modulates hippocampal synaptic strength (Hansen & Manahan-Vaughan, 2015;Kemp & Manahan-Vaughan, 2012, spike coupling of CA1 pyramidal neurons (Bacon et al, 2020) and improves memory through a β-adrenergic-dependent mechanism (Hagena et al, 2016;Hansen & Manahan-Vaughan, 2015). In agreement, we observed that the intrahippocampal blockade of β-adrenergic receptors with propranolol prevented the increase of novel object-recognition memory persistence produced by AM6545.…”

Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits

“…To assess the effect of noradrenaline on both pathways we used bath application of 20 μM noradrenaline (NA) that we have found to be a maximal effective dose for cellular and synaptic properties within hippocampal slices [ 31 ]. Application of 20 μM noradrenaline had no effect on EPSC amplitudes ( Fig 1E ; 126.1 ± 13.9% and 107.1 ± 12.1% of baseline measured at 1 st and 4th pulses, n = 14, p = 0.44) or facilitation ratios ( Fig 1E ; p = 0.08; Measured at 1 st to 4 th pulse).…”

Single-trial dynamics of hippocampal spatial representations are modulated by reward value

“…On the other hand, salience experiences also upregulate noradrenaline activity (Izquierdo and Medina 1997;Roozendaal and McGaugh 2011). Further, adrenoreceptors activation in the hippocampus increases CA1 neurons excitability (Bacon, Pickering, and Mellor 2020), promotes synaptic plasticity and memory encoding (Lemon et al 2009;Sara 2009), and is required for novelty-induced changes in hippocampal spatial code (Tanila 2001). Finally, inhibition of the locus coeruleus projections to the hippocampus, known to release both dopamine and noradrenaline (Kempadoo et al 2016; Ranjbar-Slamloo and Fazlali 2020), impairs the accumulation of fields near newly rewarded locations (Kaufman, Geiller, and Losonczy 2020).…”