title: SIRT2 inhibition modulate glutamate and serotonin systems in the prefrontal cortex and induces antidepressant-like action.
abstract: Growing evidence suggests that changes in histone acetylation in specific sites of the chromatin modulate neuronal plasticity and contribute to antidepressant-like action. Sirtuin 2 (SIRT2) is a class III NAD+-dependent histone deacetylase involved in transcriptional repression of genes regulating synaptic plasticity. Importantly, a key role for the glutamate system in prefrontal cortex (PFC) synaptic plasticity changes induced by antidepressants has been suggested. Here, we asked whether SIRT2 could be a pharmacological target for depression therapy. The compound 2-{3-(3-fluorophenethyloxy)phenylamino}benzamide (33i), a selective SIRT2 inhibitor in vitro, was studied in mice (C57Bl6). Firstly, the inhibitory effect of subchronic 33i (5-15 mg/kg, 10 days) on SIRT2 activity in the PFC was evaluated. Moreover, the effect of SIRT2 inhibition on the expression of synaptic plasticity markers linked to glutamate neurotransmission (VGLUT1, synaptophysin, mGluR4, GluA1, GluN2B, GluN2A) and on serotonin levels was studied. Further, neurochemical and behavioral effects of chronic (5 weeks) 33i (15 mg/kg) on the chronic mild stress (CMS) model were analyzed. Subchronic 33i inhibited SIRT2, increased GluN2A, GluN2B and serotonin levels in the PFC. Moreover, chronic 33i reverted CMS-induced anhedonia and social avoidance. Moreover, 33i upregulated postsynaptic GluN2B and phosphorylated form of GluA1 (p-GluA1), suggesting that SIRT2 inhibition enhance synaptic strength. Yet, CMS also increased both GluN2A and GluN2B in the postsynaptic fraction. These results suggest that Sirt2 inhibition induce antidepressant-like action and this effect could be mediated by modulation of glutamate and serotonin system in the PFC. Moreover, it highlights the therapeutic potential of SIRT2 inhibitors as new antidepressant agents.
authors.affiliation: University of Navarra, Dept. Pharmacology and Toxicology, Pamplona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Erburu
authors.affiliation: University of Navarra, Dept. Pharmacology and Toxicology, Pamplona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Muñoz-Cobo
authors.affiliation: University of Navarra, Dept. Pharmacology and Toxicology, Pamplona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Diaz-Perdigon
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mellini
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; CREST, Japan Science and Technology Agency (JST), Saitama, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: University of Navarra, Dept. Pharmacology and Toxicology, Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Puerta
authors.affiliation: University of Navarra, Dept. Pharmacology and Toxicology, Pamplona, Spain. Electronic address: rtordera@unav.es.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Tordera
mesh_terms: D059445:Anhedonia / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D013315:Stress, Psychological / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D056565:Sirtuin 2; D062367:ortho-Aminobenzoates; C000622096:2-(3-(3-fluorophenethyloxy)phenylamino)benzamide; C121001:NR2B NMDA receptor; C418743:Sirt2 protein, mouse
keywords: Chronic mild stress (CMS); Glutamate; Major depression; NMDA receptors; SIRT2