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Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity

Lookup NU author(s): Dr Rolando Berlinguer Palmini



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.

Publication metadata

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


DOI: 10.1085/jgp.201411330


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