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LC-derived excitatory synaptic transmission to dorsal raphe serotonin neurons is inhibited by activation of alpha2-adrenergic receptors

Neuropsychopharmacology volume 49, pages 1014–1023 (2024)Cite this article

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Abstract

In the central nervous system, noradrenaline transmission controls the degree to which we are awake, alert, and attentive. Aberrant noradrenaline transmission is associated with pathological forms of hyper- and hypo-arousal that present in numerous neuropsychiatric disorders often associated with dysfunction in serotonin transmission. In vivo, noradrenaline regulates the release of serotonin because noradrenergic input drives the serotonin neurons to fire action potentials via activation of excitatory α1-adrenergic receptors (α1-AR). Despite the critical influence of noradrenaline on the activity of dorsal raphe serotonin neurons, the source of noradrenergic afferents has not been resolved and the presynaptic mechanisms that regulate noradrenaline-dependent synaptic transmission have not been described. Using an acute brain slice preparation from male and female mice and electrophysiological recordings from dorsal raphe serotonin neurons, we found that selective optogenetic activation of locus coeruleus terminals in the dorsal raphe was sufficient to produce an α1-AR-mediated excitatory postsynaptic current (α1-AR-EPSC). Activation of inhibitory α2-adrenergic receptors (α2-AR) with UK-14,304 eliminated the α1-AR-EPSC via presynaptic inhibition of noradrenaline release, likely via inhibition of voltage-gated calcium channels. In a subset of serotonin neurons, activation of postsynaptic α2-AR produced an outward current through activation of GIRK potassium conductance. Further, in vivo activation of α2-AR by systemic administration of clonidine reduced the expression of c-fos in the dorsal raphe serotonin neurons, indicating reduced neural activity. Thus, α2-AR are critical regulators of serotonin neuron excitability.

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Fig. 1: Selective activation of LC system noradrenergic axons in the dorsal raphe produces an α1-AR-EPSC.
Fig. 2: Activation of α2-AR inhibits the α1-AR-EPSC via a presynaptic mechanism.
Fig. 3: Inhibitory effect of α2-AR activation does not depend on membrane potential of innervating axon terminals.
Fig. 4: Activation of α2-AR produces GIRK-mediated outward current in a subset of serotonin neurons.
Fig. 5: In vivo activation of α2-AR reduces c-fos expression in dorsal raphe serotonin neurons.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

A portion was supported by the Intramural Research Program at the National Institute on Drug Abuse (H.S.H and S.C.G). The opinions expressed in this article are the authors’ own and do not reflect the views of the NIH/DHHS. The present address for H.S.H. is in the Department of Psychology, University of Washington, Seattle, Washington, 98195, USA. We would like to thank Drs. Yeka Aponte (NIH) and Brenton Laing (University of Mississippi) for providing materials and expertise for the retrograde labeling experiments. We would like to thank the Gantz lab members, Jacqueline Khamma, Nora O’Prey, Addison Eckard, Jeff Rudman, Kathryn Cochrane, and Andrew Kain for their technical assistance in c-fos immunohistochemistry and analysis.

Funding

This research was funded by a startup award from the University of Iowa Carver College of Medicine to S.C.G. and the Carver College of Medicine and Iowa Neuroscience Institute Carver Trust Early-Stage Investigator award to S.C.G.

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  1. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, 52242, USA

    Aleigha Gugel, Erik A. Ingebretsen & Stephanie C. Gantz

  2. Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, 52242, USA

    Aleigha Gugel, Erik A. Ingebretsen & Stephanie C. Gantz

  3. National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA

    Holly S. Hake

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Aleigha Gugel: Substantial contributions to the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; and Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Erik A. Ingebretsen: Substantial contributions to the acquisition, analysis, or interpretation of data for the work; Final approval of the version to be published; and Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Holly S. Hake: Substantial contributions to the acquisition, analysis, or interpretation of data for the work; Final approval of the version to be published; and Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Stephanie C. Gantz: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; and Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Gugel, A., Ingebretsen, E.A., Hake, H.S. et al. LC-derived excitatory synaptic transmission to dorsal raphe serotonin neurons is inhibited by activation of alpha2-adrenergic receptors. Neuropsychopharmacol. 49, 1014–1023 (2024). https://doi.org/10.1038/s41386-024-01824-3

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