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Mol Metab. 2017 Jun 7;6(8):909-921. doi: 10.1016/j.molmet.2017.06.002. eCollection 2017 Aug.

Serotonergic modulation of the activity of GLP-1 producing neurons in the nucleus of the solitary tract in mouse.

Author information

1
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6BT, UK.
2
Cardiovascular Medicine, Human Physiology and Centre for Neuroscience, Flinders University, Bedford Park, SA 5042, Australia.
3
Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
4
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6BT, UK. Electronic address: s.trapp@ucl.ac.uk.

Abstract

OBJECTIVE:

Glucagon-like peptide-1 (GLP-1) and 5-HT are potent regulators of food intake within the brain. GLP-1 is expressed by preproglucagon (PPG) neurons in the nucleus tractus solitarius (NTS). We have previously shown that PPG neurons innervate 5-HT neurons in the ventral brainstem. Here, we investigate whether PPG neurons receive serotonergic input and respond to 5-HT.

METHODS:

We employed immunohistochemistry to reveal serotonergic innervation of PPG neurons. We investigated the responsiveness of PPG neurons to 5-HT using in vitro Ca2+ imaging in brainstem slices from transgenic mice expressing the Ca2+ indicator, GCaMP3, in PPG neurons, and cell-attached patch-clamp recordings.

RESULTS:

Close appositions from 5-HT-immunoreactive axons occurred on many PPG neurons. Application of 20 μM 5-HT produced robust Ca2+ responses in NTS PPG dendrites but little change in somata. Dendritic Ca2+ spikes were concentration-dependent (2, 20, and 200 μM) and unaffected by blockade of glutamatergic transmission, suggesting 5-HT receptors on PPG neurons. Neither activation nor blockade of 5-HT3 receptors affected [Ca2+]i. In contrast, inhibition of 5-HT2 receptors attenuated increases in intracellular Ca2+ and 5-HT2C receptor activation produced Ca2+ spikes. Patch-clamp recordings revealed that 44% of cells decreased their firing rate under 5-HT, an effect blocked by 5-HT1A receptor antagonism.

CONCLUSIONS:

PPG neurons respond directly to 5-HT with a 5-HT2C receptor-dependent increase in dendritic [Ca2+]i. Electrical responses to 5-HT revealed additional inhibitory effects due to somatic 5-HT1A receptors. Reciprocal innervation between 5-HT and PPG neurons suggests that the coordinated activity of these brainstem neurons may play a role in the regulation of food intake.

KEYWORDS:

5-HT, 5-hydroxytryptamine; CCK-8, cholecystokinin-8; CNS, central nervous system; Dendritic calcium; GCaMP; GLP-1, glucagon-like peptide-1; HPA, hypothalamic–pituitary–adrenal; IRT, intermediate reticular nucleus; NTS; NTS, nucleus tractus solitarius; PBN, parabrachial nucleus; PPG, preproglucagon; Preproglucagon; Serotonin; YFP, yellow fluorescent protein

PMID:
28752054
PMCID:
PMC5518719
DOI:
10.1016/j.molmet.2017.06.002
[Indexed for MEDLINE]
Free PMC Article

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