The incretin hormone glucagonlike peptide 1 increases mitral cell excitability by decreasing conductance of a voltagedependent potassium channel

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 C © 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society DOI: 10.1113/JP272322 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2608 N. Thiebaud and others J Physiol 594.10 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. (Resubmitted 15 January 2016; accepted after revision 25 February 2016; first published online 2 March 2016) Corresponding author N. Thiebaud: Florida State University, 319 Stadium Drive, King Life Sciences Building, Suite 3007, Tallahassee, FL 32306, USA. Email: thiebaud@neuro.fsu. edu Abbreviations aCSF, artificial cerebral spinal fluid; AP, action potential; AVMA, American Veterinary Medicine Association; ASPA, Animals Scientific Procedures Act; DAPI, 4′,6-diamidino-2-phenylindole; dSAC, deep short axon cell; Ex4, exendin-4; EPL, external plexiform layer; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide 1 receptor; GCL, granule cell layer; GFP, green fluorescent protein; ISI, interspike interval; IACUC, Institutional Animal Care and Use Committee; Kv1.3−/−, Kv1.3 gene-targeted deletion; MGTX, margatoxin; MC, mitral cell; MCL, mitral cell layer; OB, olfactory bulb; OMP, olfactory marker protein; PBS, phosphate-buffered saline; PFA, paraformaldehyde; PPG, preproglucagon; RMP, resting membrane potential; WT, wild-type; YFP, yellow fluorescent protein.