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The incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel.

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Peer-reviewed

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Article

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Authors

Thiebaud, Nicolas 
Llewellyn-Smith, Ida J 
Trapp, Stefan 

Abstract

KEY POINTS: The gut hormone called glucagon-like peptide 1 (GLP-1) is a strong moderator of energy homeostasis and communication between the peripheral organs and the brain. GLP-1 signalling occurs in the brain; using a newly developed genetic reporter line of mice, we have discovered GLP-synthesizing cells in the olfactory bulb. GLP-1 increases the firing frequency of neurons (mitral cells) that encode olfactory information by decreasing activity of voltage-dependent K channels (Kv1.3). Modifying GLP-1 levels, either therapeutically or following the ingestion of food, could alter the excitability of neurons in the olfactory bulb in a nutrition or energy state-dependent manner to influence olfactory detection or metabolic sensing. The results of the present study uncover a new function for an olfactory bulb neuron (deep short axon cells, Cajal cells) that could be capable of modifying mitral cell activity through the release of GLP-1. This might be of relevance for the action of GLP-1 mimetics now widely used in the treatment of diabetes. ABSTRACT: The olfactory system is intricately linked with the endocrine system where it may serve as a detector of the internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU-yellow fluorescent protein mice that express a genetic reporter under the control of the preproglucagon reporter suggested the presence of the gut hormone, glucagon-like peptide (GLP-1), in deep short axon cells (Cajal cells) of the olfactory bulb and its neuromodulatory effect on mitral cell (MC) first-order neurons. A MC target for the peptide was determined using GLP-1 receptor binding assays, immunocytochemistry for the receptor and injection of fluorescence-labelled GLP-1 analogue exendin-4. Using patch clamp recording of olfactory bulb slices in the whole-cell configuration, we report that GLP-1 and its stable analogue exendin-4 increase the action potential firing frequency of MCs by decreasing the interburst interval rather than modifying the action potential shape, train length or interspike interval. GLP-1 decreases Kv1.3 channel contribution to outward currents in voltage clamp recordings as determined by pharmacological blockade of Kv1.3 or utilizing mice with Kv1.3 gene-targeted deletion as a negative control. Because fluctuations in GLP-1 concentrations monitored by the olfactory bulb can modify the firing frequency of MCs, olfactory coding could change depending upon nutritional or physiological state. As a regulator of neuronal activity, GLP-1 or its analogue may comprise a new metabolic factor with a potential therapeutic target in the olfactory bulb (i.e. via intranasal delivery) for controlling an imbalance in energy homeostasis.

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Keywords

Action Potentials, Animals, Dose-Response Relationship, Drug, Female, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Incretins, Kv1.3 Potassium Channel, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Olfactory Bulb, Organ Culture Techniques

Journal Title

Journal of Physiology

Conference Name

Journal ISSN

0928-4257
1469-7793

Volume Title

594

Publisher

Elsevier
Sponsorship
Medical Research Council (MC_UU_12012/3)
Medical Research Council (MC_PC_12012)
This work was supported by NIH R01 DC013080 and DC003387 from the NIDCD, an American Heart Association (AHA) Postdoctoral Grant Award 14POST20380615, a Creative Research Council (CRC) award from FSU, a grant from the Medical Research Council, UK (MR/J013293/1) and support from the National Health and Medical Research Council of Australia, Project Grant #1025031. PPG-YFP mice, expressing the YFP variant Venus under the control of the mouse proglucagon promoter (mGLU124 line), were generated with grant support from the Wellcome Trust