Olivier  Manzoni
  • E-mail :[email]
  • Phone : +33 4 91 82 81 37
  • Location : Marseille, France
Last update 2018-01-18 15:25:08.332

Olivier Manzoni Adolescence and developemental vulnerability to neuropsychiatric diseases

Course and current status

Degrees

  • 1992: Ph.D. Biochemistry, Molecular and Cellular Biology, Université de Montpellier

 Career

  • Tenure Position « Chargé de Recherches CR2 » INSERM 1993
  • 1993-1995: Post-Doctoral Fellow, University of California San Francisco (USA). Department of Pharmacology and Physiology in Dr. R.A Nicoll laboratory. Synaptic plasticity in the hippocampus. INSERM post-doctoral fellow 1993-1994.
  • 1997-1999: Visiting Scientist, Vollum Institute (Portland, OR, USA) in Dr. J. Williams’ laboratory. Synaptic plasticity induced by chronic morphine treatment in the Ventral tegmental area and the hippocampus. NIDA/INVEST fellow.
  • Promoted Chargé de Recherches CR1 INSERM 1998
  • Promoted Directeur de Recherches DR2 INSERM 2002.
  • Promoted Directeur de Recherches DR1 INSERM 2010.

 

Direction appointments

  • 2002: Group Leader Equipe AVENIR INSERM Bordeaux.
  • 2005: Funding Group Leader INSERM U862 Bordeaux.
  • 2010: Team Physiopathology of Synaptic Plasticity, INMED INSERM U901 Marseille.
  • 2017: Team Adolescence and developmental vulnerability to neuropsychiatric diseases, INMED INSERM U1249 Marseille.
  • 2017: Director Cannabinoid Neuroscience Research International Associated Laboratory INSERM- Indiana University USA.

 

Relationships with Pharmaceutical companies

  • SANOFI-AVENTIS: Consultant 2007-2008-2009.
  • Scientiae: Consultant 2007-2008.

Awards

  • 1997: NIDA/INVEST Fellowship. 
  • 2010:  NARSAD Independent Investigator.
  • 2017:  International Associated Laboratory INSERM-Indiana University USA.

 Member of Editorial board

  • eLife
  • Neuropharmacology

 Grant Committees and research orientation

  • Fondation Lejeune (Scientific Committee): 2011-Present
  • USA-Israel Binational Science Fundation: 2016-Present
  • Comité Evaluation ANR Blanc 2011.
  • Commission de Spécialistes n° 69 Neuroscience Université de Bordeaux II, 2007 & 2009.
  • Comité AERES/INSERM 2008.
  • Welcome Trust.
  • Medical Research Council.
  • Ville de Paris.
  • Région PACA.
  • Fondation pour la Recherche sur le Cerveau. 

Fundings:

Ongoing Research Support

  • NIH NIDA : 1R01DA043982-01A1; Manzoni, Olivier (PI); 01/08/17-31/05/22
  • Equipe FRM 2015, Fondation pour la Recherche Medicale; O. Manzoni (PI)
  • Agence Nationale pour la Recherche: A-L. Pellissier, (Coordinator) ; Cannado

Completed Research Support 2012-2017

  • Agence Nationale de la Recherche; O. Manzoni (Coordinator) ; MoodFood: Depression and Nutrition
  • Agence Nationale de la Recherche; B. Bardoni (Coordinator); Cyfip-Aut: Role of CYFIP1 in physiopathology of autism & mental retardation
  • Fondation Jerome Lejeune: O. Manzoni (PI) ; Multiscale analysis of Down Syndrome Synaptopathies
  • ARSEP: O. Manzoni & C. Matute (Co-PI); Monoacylglycerol lipase inhibition for the treatment of multiple sclerosis

Scientific Societies

  • Société Française des Neurosciences
  • Society for Neurosciences USA

 Scientific production:

86 publications 1989-Present; Citations: 7948; h index: 47.

10 best publications 2007-2017

1- Kasanetz F… Manzoni O #, Piazza PV #. Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science. 2010 Jun 25;328(5986):1709-12. # Shared Seniority

2- Lafourcade M,… Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nature Neurosci. 2011 Mar;14(3):345-50.

3- Puente N, … Manzoni OJ. Polymodal activation of the endocannabinoid system in the extended amygdala. Nature Neurosci. 2011 Nov 6;14(12):1542-7.

4- Jung KM, …, Manzoni OJ. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nature Commun. 2012;3:1080.

5- Bosch-Bouju C, … Manzoni OJ #, Layé S #. Endocannabinoid-Mediated Plasticity in Nucleus Accumbens Controls Vulnerability to Anxiety after Social Defeat Stress. Cell Rep. 2016 Aug 2;16(5):1237-1242. # Shared Seniority

6- Martin HGS, Lassalle O, Brown JT, Manzoni OJ. Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome. Cereb Cortex. 2016 May;26(5):2084-2092.

7- Martin HGS, Lassalle O, Manzoni OJ. Differential Adulthood Onset mGlu5 Signaling Saves Prefrontal Function in the Fragile X Mouse. Cereb Cortex. 2017 Dec 1;27(12):5592-5602.

8- Mikasova L, Groc L, Choquet D, Manzoni OJ. Altered surface trafficking of presynaptic cannabinoid type 1 receptor in and out synaptic terminals parallels receptor desensitization. Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18596-601.

9- Manduca A,… Manzoni OJ. Amplification of mGlu5-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance. J Neurosci. 2017 Jul 19;37(29):6851-6868.

10- Thomazeau A, … J, Manzoni OJ. Prefrontal deficits in a murine model overexpressing the down syndrome candidate gene dyrk1a. J Neurosci. 2014 Jan 22;34(4):1138-47.

 Reviewer

  • Neuron
  • eLife
  • Nature Neuroscience
  • Proceedings of the National Academy of Sciences (U.S.A.)
  • Journal of Neuroscience
  • Biological Psychiatry
  • Journal of Neurophysiology
  • Trends in Neurosciences
  • Learning and Memory
  • Journal of Physiology
  • Neuropharmacology
  • Neuropsychopharmacology
  • European Journal of Neuroscience
  • Molecular Pharmacology
  • Brain Research
  • Journal of Neurochemistry
  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology  
  • PLoS ONE  
  • Frontiers in Neurosciences

 

  Technical expertise

  • Electrophysiology
  • Imaging (in vitro & in vivo)
  • Behavior
  • Synaptopathology. 

Scientific summary

Scientific background:

For the past fifteen years, the research activity in our laboratory was centred on understanding the molecular basis of synaptic plasticity in normal and pathological conditions, with a focus on glutamatergic synaptic microcircuits since they are instrumental to synaptic plasticity, learning and memory. To describe the relationship between the structural and functional plasticity of glutamatergic synapses and brain functions (memory, cognition, reward)/dysfunctions (depression; mental retardation; schizophrenia, addiction) we had developed over the years an integrated experimental approach combining cellular biology, biochemistry, electrophysiology and optical techniques to identify metaplastic adaptations in original environmental/genetic models of neuropsychiatric diseases. We made several important discoveries: 1/ we made a major conceptual advance in the field of addiction by showing that in cocaine addicted rats, allostatic adaptations keep synapses in a state of non-plasticity (Science 2010); 2/ we also discovered that the surface dynamics of the most abundant G-protein coupled receptor (GPCR) of the CNS, the CB1R are altered following exposure to psychoactive cannabinoid and based on our work proposed a general desensitization mechanism for GPCRs (PNAS 2008; Nature Neuroscience 2004). 3/ We have elucidated a molecular mechanism leading to the postnatal maturation of synapses in the hippocampus and found that Reelin, an ECM protein and major psychiatric risk factor, governs the surface trafficking and subunit composition of glutamate receptors of NMDA (Sinagra et al. 2005 J. Neuroscience; Groc et al. 2007 J. Neuroscience).

Based on the realization that we needed to tightly link synaptic and behavioral phenotyping we developed in-house behavioral methods. This technical evolution allowed discovering that Reelin drives the psychopathological development of the prefrontal cortex, delineates previously unknown developmental endophenotypic sequences and defines a critical window for therapeutic rehabilitation (Iafrati et al. 2013 Mol. Psychiatry; Iafrati et al. 2016 Scientific Reports; Bouamrane et al. 2016). Following a similar strategy, we deconstructed and corrected complex phenotypes and proposed new therapeutic approaches in mouse models of Fragile X and Down syndromes (Jung et al. 2012 Nature Communications Martin et al. Cerebral Cortex 2016a; Martin et al. Cerebral Cortex 2016b; Thomazeau et al, J. Neuroscience 2014) as well as major depression (Bosch-Bouju et al. Cell Reports 2016)). We showed that nutrition controls cognition and emotions. Not only does perinatal malnutrition impair hippocampal (Thomazeau et al. Cerebral Cortex 2016) and prefrontal synapses and associated behaviors (Lafourcade et al. Nature Neuroscience 2011) but we recently found that adolescent vulnerability to dietary polyunsaturated fatty acids deficiency implicates the endocannabinoid system (Manduca et al. 2017 J. Neuroscience). Finally, we found that adolescent vulnerability to high-fat diet is mediated by reelin expressing prefrontal neurons, showing the enthusing convergence of our research lines (Labouesse et al. Mol. Psychiatry 2016). These are important breakthroughs at the core of our working hypothesis on genetic vulnerability to neuropsychiatric disorders

Current research project:

Our general aim is to understand how meso-corticolimbic (MCL) microcircuits are shaped throughout early life critical periods especially adolescence, to give rise to harmonious emotional behaviors and cognitive functions in adulthood. Specifically, we want to understand how environmental and genetic insults modelling neuropsychiatric diseases transform the architecture and the functionality of synaptic networks and reduce behavioral flexibility.

Early post-natal periods are common periods of vulnerability to the development of early and late-onset neuropsychiatric diseases. Our previous work fuelled the concept that structural and functional damages during early life periods including adolescence are causal in disease-linked behavioral deficits. Our core hypothesis is that adolescence delineates a period of maximal vulnerability and consequently is a critical determinant of how environments and genes shape neuronal network functions into adulthood (Labouesse et. al. Mol. Psy. 2016).

Our project is organized in three objectives: first, we systematically audit structural and functional properties to determine how development shapes MCL microcircuits; second, we correlate neuronal and synaptic activities to behavioral flexibility in health and disease and finally, we use optogenetic stimulation and pharmacological modulation of specific neuronal microcircuits to recreate/compensate/reactivate behavioral flexibility in diseased mice.

We analyze longitudinally (from pre-puberty to adulthood) the architectural, functional and behavioral flexibility of MCL networks (mostly focusing on the prefrontal cortex and the nucleus accumbens) in vitro and in vivo, in clinically relevant models of neuropsychiatric diseases with known adolescent component. Based on our large expertise we use mouse models of gene candidates for autism and schizophrenia (reeler-/+; perineuronal nets; frm1-/y) and environmental insults (malnutrition; cannabis; social isolation; inflammation).

To describe how adolescence shapes MCL networks, we apply a multidisciplinary approach that combines in vitro and in vivo, electrophysiology, ablation by toxin receptor cell targeting of selected neuronal population, in vivo calcium imaging, quantitative tridimensional neuroanatomy, whole brain clarifying procedures and light-sheet microscopy; optogenetics and the analysis of naturalistic behaviors across the emotional and cognitive domains. To consider the multidimensional nature of the data and evaluate the interrelationship between structural, functional and behavioral parameters, we use a general strategy that we recently conceived, based on multivariate analysis of bootstrapped datasets (Iafrati et al. 2016, Scientific Reports). Our research project will allow disambiguating complex phenotypes into new developmental endophenotypes and rational design of innovative therapeutic strategies

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