Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences

Nicolas Narboux-Nême (1) , Corinne Sagné (2) , Stephane Doly (1) , Silvina L Diaz (1) , Cédric Bp Martin (3) , Gaelle Angenard (1) , Marie-Pascale Martres (4) , Bruno Giros (4, 5) , Michel Hamon (3) , Laurence Lanfumey (3) , Patricia Gaspar (1) , Raymond Mongeau (3)

1 Institut du Fer à Moulin
2 UMR 8192 - Laboratoire de dynamique membranaire et maladies neurologiques
3 U894 - Centre de Psychiatrie et Neurosciences
4 Physiopathologie des Maladies du Système Nerveux Central
5 Department of Psychiatry [Montréal]

The vesicular monoamine transporter type 2 gene (VMAT2) plays 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 the control of the serotonin transporter (slc6a4) promoter. VMAT2sert-cre mice showed a major (-95%) depletion of 5-HT levels in the brain with no major alterations of the other monoamines. Raphe neurons contained no 5-HT immunoreactivity in VMAT2sert-cre mice but developed normal innervations, as assessed by both tryptophan hydroxylase 2 and 5-HT transporter labeling. Increased 5-HT1A autoreceptor coupling to G protein, as assessed with agonist stimulated [35S]GTP-γ-S binding, was observed in the raphe area, indicating an adaptive change to the reduced 5-HT transmission. Behavioral evaluation in adult VMAT2sert-cre mice showed an increase of 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, VMAT2sert-cre mice displayed a major increase of 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, albeit in reduced amount, in synaptosomes from VMAT2sert-cre mice brain. These findings are coherent with the notion that 5-HT plays an important role in anxiety, and provide new insights on the role of endogenous 5-HT in defense behaviors.

Mots clés: Stress Disorders; Anxiety; Mood; Biological Psychiatry; Serotonin; Animal models; knockout mice; vesicular monoamine transporter; serotonin transporter; 5-HT1A receptors; raphe

Domaines: Pharmacologie

Nicolas Narboux-Nême, Corinne Sagné, Stephane Doly, Silvina L Diaz, Cédric Bp Martin, et al.. Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences. Neuropsychopharmacology, 2011, 36, pp.2538-2550. ⟨10.1038/npp.2011.142⟩. ⟨hal-00665880⟩