title: Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression.
abstract: Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naïve DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naïve animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.
authors.affiliation: Faculté de Médecine, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg Strasbourg, France.
authors.forename: Brandon H
authors.initials: BH
authors.lastname: Cline
authors.affiliation: Department of Neuroscience, Maastricht University Maastricht, Netherlands ; Group of Behavioural Neuroscience and Pharmacology, Institute for Hygiene and Tropical Medicine, New University of Lisbon Lisbon, Portugal.
authors.forename: Joao P
authors.initials: JP
authors.lastname: Costa-Nunes
authors.affiliation: Faculty of Medicine, Neuroscience Research Center of Lyon, INSERM U1028, C. Bernard University Lyon, France.
authors.forename: Raymond
authors.initials: R
authors.lastname: Cespuglio
authors.affiliation: Laboratory of Biomolecular Screening, Institute of Physiologically Active Compounds, Russian Academy of Sciences Moscow, Russia ; Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences Moscow, Russia.
authors.forename: Natalyia
authors.initials: N
authors.lastname: Markova
authors.affiliation: Faculdade de Ciências Médicas, NOVA Medical School, Universidade Nova de Lisboa Lisboa, Portugal.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Santos
authors.affiliation: Great Lakes Bioenergy Research Center, Computational Biology, Wisconsin Energy Institute, University of Wisconsin Madison, WI, USA.
authors.forename: Yury V
authors.initials: YV
authors.lastname: Bukhman
authors.affiliation: Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences Moscow, Russia.
authors.forename: Aslan
authors.initials: A
authors.lastname: Kubatiev
authors.affiliation: Department of Neuroscience, Maastricht University Maastricht, Netherlands.
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Department of Neuroscience, Maastricht University Maastricht, Netherlands ; Laboratory of Translational Neuroscience, Division of Molecular Psychiatry, Centre of Mental Health, University of Wuerzburg Wuerzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Neuroscience, Maastricht University Maastricht, Netherlands ; Group of Behavioural Neuroscience and Pharmacology, Institute for Hygiene and Tropical Medicine, New University of Lisbon Lisbon, Portugal ; Laboratory of Biomolecular Screening, Institute of Physiologically Active Compounds, Russian Academy of Sciences Moscow, Russia.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
keywords: NMDA receptor subunits NR2A and NR2B; aging; chronic stress; dicholine succinate; hippocampal plasticity; insulin receptor; phosphorylated glycogen synthase kinase-3beta (pGSK-3beta); sleep EEG