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Lookup NU author(s): Dr Rolando Berlinguer PalminiORCiD
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (CC BY-SA 4.0).
The firing activity of serotonergic neurons in raphe nuclei is regulated by negative feedback exerted by extracellular serotonin (5-HT)o acting through somatodendritic 5-HT1A autoreceptors. The steady-state [5-HT]o, sensed by 5-HT1A autoreceptors, is determined by the balance between the rates of 5-HT release and reuptake. Although it is well established that reuptake of 5-HTo is mediated by 5-HT transporters (SERT), the release mechanism has remained unclear. It is also unclear how selective 5-HT reuptake inhibitor (SSRI) antidepressants increase the [5-HT]o in raphe nuclei and suppress serotonergic neuron activity, thereby potentially diminishing their own therapeutic effect. Using an electrophysiological approach in a slice preparation, we show that, in the dorsal raphe nucleus (DRN), continuous nonexocytotic 5-HT release is responsible for suppression of phenylephrine-facilitated serotonergic neuron firing under basal conditions as well as for autoinhibition induced by SSRI application. By using 5-HT1A autoreceptor-activated G protein-gated inwardly rectifying potassium channels of patched serotonergic neurons as 5-HTo sensors, we show substantial nonexocytotic 5-HT release under conditions of abolished firing activity, Ca(2+) influx, vesicular monoamine transporter 2-mediated vesicular accumulation of 5-HT, and SERT-mediated 5-HT transport. Our results reveal a cytosolic origin of 5-HTo in the DRN and suggest that 5-HTo may be supplied by simple diffusion across the plasma membrane, primarily from the dense network of neurites of serotonergic neurons surrounding the cell bodies. These findings indicate that the serotonergic system does not function as a sum of independently acting neurons but as a highly interdependent neuronal network, characterized by a shared neurotransmitter pool and the regulation of firing activity by an interneuronal, yet activity-independent, nonexocytotic mechanism.
Author(s): Mlinar B, Montalbano A, Baccini G, Tatini F, Berlinguer-Palmini R, Corradetti R
Publication type: Article
Publication status: Published
Journal: Journal of General Physiology
Year: 2015
Volume: 145
Issue: 3
Pages: 225-251
Print publication date: 01/03/2015
Online publication date: 23/02/2015
Acceptance date: 30/01/2015
Date deposited: 19/03/2015
ISSN (print): 0022-1295
ISSN (electronic): 1540-7748
Publisher: The Rockefeller University Press
URL: http://dx.doi.org/10.1085/jgp.201411330
DOI: 10.1085/jgp.201411330
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