title: The incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel.
abstract: 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.
  
  
  
  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.
authors.affiliation: The Florida State University, Department of Biological Science, Program in Neuroscience, Tallahassee, FL, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Thiebaud
authors.affiliation: Cardiovascular Medicine and Human Physiology, School of Medicine, Flinders University, Bedford Park, SA, Australia.
authors.forename: Ida J
authors.initials: IJ
authors.lastname: Llewellyn-Smith
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Gribble
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK.|Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Trapp
authors.affiliation: The Florida State University, Department of Biological Science, Program in Neuroscience, Tallahassee, FL, USA.|The Florida State University, Institute of Molecular Biophysics, Tallahassee, FL, USA.
authors.forename: Debra Ann
authors.initials: DA
authors.lastname: Fadool
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000172:deficiency; D054795:Incretins / Q000494:pharmacology*; D051664:Kv1.3 Potassium Channel / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009830:Olfactory Bulb / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D051664:Kv1.3 Potassium Channel; D052216:Glucagon-Like Peptide 1