title: Regulation of serotonin (5-HT) function by a VGLUT1 dependent glutamate pathway.
abstract: Unraveling the mechanisms of 5-HT neuron control might provide new insights into depression pathophysiology. In addition to the inhibitory 5-HT1A autoreceptors, cortico-raphe glutamatergic descending pathways are suggested to modulate 5-HT activity in the DRN. Here we studied how decreased VGLUT1 levels in the brain stem affect glutamate regulation of 5-HT function. VGLUT1+/- mice (C57BL/6) and wild type (WT) littermates were used. VGLUT1 expression in the DRN, 5-HT turnover and immuno histochemical analysis of neuronal activity in different areas was studied. Moreover, the functionality of the inhibitory 5-HT1A autoreceptor was assessed using electrophysiological, biochemical and pharmacological approaches. VGLUT1 immunoreactivity was markedly lower in the DRN of the VGLUT1+/- mice and specifically, in the surroundings of GABA and 5-HT cell bodies. These mice showed decreased induced neuronal activity in 5-HT cells bodies and in different forebrain areas, as well as decreased hippocampal cell proliferation and 5-HT turnover. Further, 5-HT1A autoreceptor desensitization was evidenced by electrophysiological studies, GTP-γ-S coupling to 5-HT1A autoreceptor and a lower hypothermic response to 5-HT1A activation. This study shows first time that VGLUT1 dependent glutamate innervation of the DRN could modulate 5-HT function.
authors.affiliation: University of Navarra, Department of Pharmacology, Irunlarrea SN, 31080 Pamplona, Spain.
authors.forename: Alvaro L
authors.initials: AL
authors.lastname: García-García
authors.forename: Elisabet
authors.initials: E
authors.lastname: Venzala
authors.forename: Natalia
authors.initials: N
authors.lastname: Elizalde
authors.forename: M J
authors.initials: MJ
authors.lastname: Ramírez
authors.forename: Ahinoa
authors.initials: A
authors.lastname: Urbiola
authors.forename: Joaquin
authors.initials: J
authors.lastname: Del Rio
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Tordera
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000502:physiology; D001933:Brain Stem / Q000378:metabolism; D049109:Cell Proliferation; D015870:Gene Expression / Q000235:genetics; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology; D007035:Hypothermia / Q000503:physiopathology; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D050598:Vesicular Glutamate Transport Protein 1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D017660:Autoreceptors; D050598:Vesicular Glutamate Transport Protein 1; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D018698:Glutamic Acid