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

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

Travis J Bacon et al. Cereb Cortex. 2020.

Abstract

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.

Keywords: CA1; hippocampus; locus coeruleus; noradrenaline; synaptic transmission.

© The Author(s) 2020. Published by Oxford University Press.

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Figures

Figure 1

Figure 1

Characterization of the CAV2-PRS-mCherry-ChR2 viral vector expression in mice. (A) Schematic for viral vector injections into the Locus Coeruleus (LC). (B) mCherry fluorescence co-localized with dopamine-β-hydroxylase fluorescence, confirming successful noradrenergic neuronal targeting of the viral vector. (C) % of mCherry+ neurons also showing dopamine-β-hydroxylase expression. (D) mCherry fluorescence in LC fibers within the hippocampus confirming expression of ChR2 in axons. (E and F) Light stimulation of ChR2-mCherry-expressing LC neurons recorded in current-clamp configuration reliably elicited action potentials with stimulation frequencies up to 25 Hz after which amplitude and fidelity began to deteriorate. Scale bars = 25 mV, 200 ms.

Figure 2

Figure 2

Endogenous NA release enhances CA1 spike output via β-AR activation. (A) Schematic showing ex vivo slice recording and optogenetic stimulation. (B_–_D) Example traces (B), experiment timecourse (C) and grouped data (D) show 1 Hz tonic light stimulation (10 min, LED) to release endogenous NA enhances the spike probability in CA1 pyramidal neurons in response to Schaffer collateral synaptic stimulation (10 stimuli at 10 Hz) in slices from ChR2-injected but not WT mice. Scale bars = 25 mV, 250 ms. (E and F) Pre-incubation of slices with the β-AR antagonist, propranolol (500 nM) for 5 min prior to light stimulation blocked the increase in spike probability. Scale bars = 25 mV, 250 ms. (G and H) Phasic light stimulation (10 pulses at 25 Hz, immediately before synaptic stimuli) also increased spike probability but the increase was more variable. Scale bars = 25 mV, 250 ms.

Figure 3

Figure 3

Biphasic dose-response relationship for exogenous NA on CA1 spike output. (A_–_H) Example traces, averaged timecourse and grouped data for spike probability experiments using exogenous application of 200 nM (A and B), 600 nM (C and D), 2 μM (E and F) and 20 μM NA (G and H). (I) Percentage change in spike probability for all conditions. (J) Dose-response curve for change in spike probability with concentration of NA. Overlaid blue shading indicates the mean and SEM change in spike probability produced by 1 or 25 Hz light stimulation of endogenous NA release. Overlap between blue shading and dose-response curve indicates likely concentration of endogenous NA release. Scale bars = 20 mV, 250 ms.

Figure 4

Figure 4

Endogenous NA release has no effect on Schaffer collateral feedforward excitatory and inhibitory synaptic transmission. (A_–_C) EPSPs recorded during spike probability experiments were unaffected by endogenous NA release (A) or 600 nM NA (B) but depressed by 20 μM NA (C). Plots in A show EPSPs recorded in slices from virus injected and WT animals. Insets in panels show example EPSPs. Scale bars = 2 mV, 20 ms. (D and E) Experimentally determined reversal potentials for GABA and glutamate receptors, respectively. Current-voltage plots and example traces for IPSCs (D) and EPSCs (E). Scale bars = 200 pA and 100 ms (GABAA reversal traces), 50 pA and 100 ms (glutamate reversal traces). (F_–_H) Time-course plots showing EPSC and IPSC amplitudes and the effect of endogenous NA release (F), 600 nM (G) and 20 μM NA (H). Scale bars = 100 pA, 50 ms (both traces in H and IPSCs in F and G), 25 pA, 50 ms (EPSCs, F and G). (I_–_K) Grouped data for EPSPs (I), EPSCs (J) and IPSCs (K) for each NA application.

Figure 5

Figure 5

I sAHP currents are inhibited by exogenous 20 μM or 600 nM NA, but not endogenous NA release. (A_–_C) Timecourse and example traces showing _I_sAHP inhibition with 600 nM NA (B) and 20 μM NA (C) but not endogenous NA release in slices from virus injected mice or by light stimulation in slices from WT mice (A). Scale bars = 10 pA, 500 ms (WT), 25 pA, 500 ms (ChR2-injected), 50 pA, 500 ms (600 nM NA), 10 pA, 250 ms (20 μM NA). (D) Grouped data for virus injected and WT mice show no effect of endogenous NA release whereas both 600 nM and 20 μM NA depressed _I_sAHP when compared to a time-matched control.

Figure 6

Figure 6

Endogenous NA release does not modulate resting intrinsic cellular properties. (A_–_C) Timecourse of changes in resting membrane potential (_V_m) from baseline showing no effect of endogenous NA release (A) or 600 nM NA (B) but a hyperpolarization caused by 20 μM NA (C). (D) Group data for effects of all conditions on _V_m. (E_–_G) Timecourse of changes in input resistance (_R_in) from baseline showing no effect of endogenous NA release (E), 600 nM NA (F) and 20 μM NA (G). Example traces are inset. Scales bars = 5 mV, 200 ms. (H) Group data for effects of all conditions on _R_in.

Figure 7

Figure 7

Endogenous NA release reduces spike latency. (A and B) Spike threshold in response to evoked EPSPs was lowered by endogenous NA release (A) but not 600 nM NA (B). Spike threshold is reduced in slices from virus injected animals but not in WT animals. Example traces are inset. Scale bars = 5 mV, 0.5 ms for expanded traces and 25 mV, 5 ms otherwise. (C) Group data for spike threshold. (D_–_F) Group data and example traces showing that spike latency in response to evoked EPSPs is reduced by endogenous NA release in slices from virus injected mice (D) or 600 nM NA (F) but not by light stimulation in slices from WT mice (E). Scale bars = 25 mV, 5 ms.

Figure 8

Figure 8

Excitation-spike coupling is enhanced by endogenous NA release. (A_–_C) Example traces showing a reduction in rheobase spike latency and jitter in response to endogenous NA release (A) or 600 nM NA (B) that is blocked with propranolol (C). Scale bars = 25 mV, 250 ms. (D_–_H) Group data showing the effects of endogenous NA release and 600 nM NA and the block with propranolol on spike latency (D and E), jitter (F), charge transfer required to elicit an action potential (G) and spike threshold (H).

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References

    1. Andrade R, Foehring RC, Tzingounis AV. 2012. The calcium-activated slow AHP: cutting through the Gordian knot. Front Cell Neurosci. 6:47. - PMC - PubMed
    1. Aston-Jones G, Bloom FE. 1981. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci. 1:876–886. - PMC - PubMed
    1. Aston-Jones G, Cohen JD. 2005. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol. 493:99–110. - PubMed
    1. Bergles DE, Doze VA, Madison DV, Smith SJ. 1996. Excitatory actions of norepinephrine on multiple classes of hippocampal CA1 interneurons. J Neurosci. 16:572–585. - PMC - PubMed
    1. Berridge CW, Waterhouse BD. 2003. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev. 42:33–84. - PubMed

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