title: Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences.
abstract: The vesicular monoamine transporter type 2 gene (VMAT2) has a crucial role in the storage and synaptic release of all monoamines, including serotonin (5-HT). To evaluate the specific role of VMAT2 in 5-HT neurons, we produced a conditional ablation of VMAT2 under control of the serotonin transporter (slc6a4) promoter. VMAT2(sert-cre) mice showed a major (-95%) depletion of 5-HT levels in the brain with no major alterations in other monoamines. Raphe neurons contained no 5-HT immunoreactivity in VMAT2(sert-cre) mice but developed normal innervations, as assessed by both tryptophan hydroxylase 2 and 5-HT transporter labeling. Increased 5-HT(1A) autoreceptor coupling to G protein, as assessed with agonist-stimulated [(35)S]GTP-γ-S binding, was observed in the raphe area, indicating an adaptive change to reduced 5-HT transmission. Behavioral evaluation in adult VMAT2(sert-cre) mice showed an increase in escape-like reactions in response to tail suspension and anxiolytic-like response in the novelty-suppressed feeding test. In an aversive ultrasound-induced defense paradigm, VMAT2(sert-cre) mice displayed a major increase in escape-like behaviors. Wild-type-like defense phenotype could be rescued by replenishing intracellular 5-HT stores with chronic pargyline (a monoamine oxidase inhibitor) treatment. Pargyline also allowed some form of 5-HT release, although in reduced amounts, in synaptosomes from VMAT2(sert-cre) mouse brain. These findings are coherent with the notion that 5-HT has an important role in anxiety, and provide new insights into the role of endogenous 5-HT in defense behaviors.
authors.affiliation: INSERM, UMR-S 839, Institut du Fer à Moulin, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Narboux-Nême
authors.forename: Corinne
authors.initials: C
authors.lastname: Sagné
authors.forename: Stephane
authors.initials: S
authors.lastname: Doly
authors.forename: Silvina L
authors.initials: SL
authors.lastname: Diaz
authors.forename: Cédric B P
authors.initials: CB
authors.lastname: Martin
authors.forename: Gaelle
authors.initials: G
authors.lastname: Angenard
authors.forename: Marie-Pascale
authors.initials: MP
authors.lastname: Martres
authors.forename: Bruno
authors.initials: B
authors.lastname: Giros
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
authors.forename: Patricia
authors.initials: P
authors.lastname: Gaspar
authors.forename: Raymond
authors.initials: R
authors.lastname: Mongeau
mesh_terms: D000818:Animals; D004924:Escape Reaction / Q000502:physiology*; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D059326:Serotonergic Neurons / Q000378:metabolism* / Q000473:pathology*; D012701:Serotonin / Q000172:deficiency* / Q000235:genetics*; D012720:Severity of Illness Index; D050493:Vesicular Monoamine Transport Proteins / Q000172:deficiency* / Q000235:genetics*
chemical_list: C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin