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Scott F.F.,University of Manchester | Belle M.D.C.,University of Manchester | Delagrange P.,Institute Of Recherches Servier Idrs | Piggins H.D.,University of Manchester
Journal of Neuroendocrinology | Year: 2010

The master circadian pacemaker in the suprachiasmatic nuclei (SCN) regulates the nocturnal secretion of the pineal hormone melatonin. Melatonin, in turn, has feedback effects on SCN neuronal activity rhythms via high affinity G protein-coupled receptors (MT1 and MT2). However, the precise effects of melatonin on the electrical properties of individual SCN neurones are unclear. In the present study, we investigated the acute effects of exogenous melatonin on SCN neurones using whole-cell patch-clamp recordings in brain slices prepared from Per1::d2EGFP-expressing transgenic mice. In current-clamp mode, bath applied melatonin, at near-physiological concentrations (1 nm), hyperpolarised the majority (63.7%) of SCN neurones tested at all times of the projected light/dark cycle. In addition, melatonin depolarised a small proportion of cells (11.0%). No differences were observed for the effects of melatonin between Per1::GFP or non-Per1::GFP SCN neurones. Melatonin-induced effects were blocked by the MT1/MT2 antagonist, luzindole (1 μm) and the proportion of SCN neurones responsive to melatonin was greatly reduced in the presence of either tetrodotoxin (200 or 500 nm) or gabazine (20 μm). In voltage-clamp recordings, 1 nm melatonin increased the frequency of GABA-mediated currents. These findings indicate, for the first time, that exogenous melatonin can alter neuronal excitability in the majority of SCN neurones, regardless of whether or not they overtly express the core clock gene Per1. The results also suggest that melatonin acts mainly by modulating inhibitory GABAergic transmission within the SCN. This may explain why exogenous application of melatonin has heterogenous effects on individual SCN neurones. © 2010 The Authors. Journal of Neuroendocrinology © 2010 Blackwell Publishing Ltd.

Zhang H.,Institut Universitaire de France | Zhang H.,French National Center for Scientific Research | Etherington L.-A.,University of Dundee | Hafner A.-S.,Institut Universitaire de France | And 12 more authors.
Molecular Psychiatry | Year: 2013

The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, 3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity. © 2013 Macmillan Publishers Limited.

Canet E.,Institute Of Recherches Internationales Servier Iris | Lerebours G.,Institute Of Recherches Internationales Servier Iris | Vilaine J.-P.,Institute Of Recherches Servier Idrs
Annals of the New York Academy of Sciences | Year: 2011

The link between elevated heart rate and cardiovascular events is established in healthy individuals and in patients with cardiovascular disease. The new agent, ivabradine, specifically and selectively inhibits the I f current, with the sole action of heart rate reduction, with no impact on any other cardiac parameters. The benefits of "pure" heart rate reduction with ivabradine have been the focus of one of the largest clinical development programs ever performed, involving >20,000 individuals. Ivabradine has anti-ischemic and antianginal efficacy in monotherapy, as well as in combination with other antianginals, such as beta-blockers, and is safe and well tolerated. Two major morbidity-mortality trials, BEAUTIFUL and SHIFT, showed that heart rate reduction with ivabradine dramatically improves prognosis in patients with coronary artery disease and left ventricular dysfunction, symptomatic angina, or chronic heart failure. The development of ivabradine represents a clear innovation in the management of cardiovascular disease. © 2011 New York Academy of Sciences.

Petit L.,Ecole Polytechnique - Palaiseau | Botez I.,Institute Of Recherches Servier Idrs | Tizot A.,Institute Of Recherches Servier Idrs | Zard S.Z.,Ecole Polytechnique - Palaiseau
Tetrahedron Letters | Year: 2012

Variously substituted novel dihydropyridoazepinones have been prepared by an intermolecular radical addition followed by a radical cyclisation on a pyridine ring. The latter process involved the use of a combination of two different peroxides, an experimental contrivance resulting from a careful product analysis and a better understanding of the cyclisation step. © 2012 Elsevier Ltd. All rights reserved.

Ingallinesi M.,French Institute of Health and Medical Research | Le Bouil L.,French Institute of Health and Medical Research | Faucon Biguet N.,French Institute of Health and Medical Research | Do Thi A.,French Institute of Health and Medical Research | And 6 more authors.
Molecular Psychiatry | Year: 2014

Gpr88, an orphan G-protein-coupled receptor, is highly and almost exclusively expressed in the medium spiny projection neurons of the striatum, and may thus participate in the control of motor functions and cognitive processing that are impaired in neuropsychiatric disorders such as Parkinson's disease or schizophrenia (SZ). This study investigated the relevance of Gpr88 to SZ-associated behavior by knocking down Gpr88 gene expression in the ventral striatum (nucleus accumbens) in a neurodevelopmental rat model of SZ, generated by neonatal treatment with phencyclidine (PCP). In this model, we compared the effects of the local inactivation in the adult animal of the expression of Gpr88 and of Drd2, a gene strongly implicated in the etiology of SZ and coding for the dopamine receptor type 2 (D2). To inactivate specifically Gpr88 and D2 expression, we used the lentiviral vector-mediated microRNA silencing strategy. The neonatal PCP treatment induced in the adult rat hyperlocomotion in response to amphetamine (Amph) and social novelty discrimination (SND) deficits. The inactivation of D2 did not modify the locomotor response to Amph or the cognitive deficits induced by PCP, whereas the silencing of Gpr88 inhibited the Amph-induced hyperlocomotion and reduced the impairment of SND elicited by neonatal exposure to PCP. These observations suggest a role for Gpr88 in the regulation of cognitive and motor functions, and support its relevance to the pathophysiology and treatment of SZ and other disorders involving dysfunction of the accumbens-striatal complex.Molecular Psychiatry advance online publication, 26 August 2014; doi:10.1038/mp.2014.92.

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