Team Krebs

Pathophysiology of Psychiatric disorders :Development and Vulnerability


Team leader :  Marie-Odile Krebs

Team member :  Charlotte Alexandre  |   Isabelle Amado  |   Narjes Bendjemaa  |   Pauline Chaste  |   Boris Chaumette  |   Macarena Cuenca-Maia  |   Ghita Dadi  |   Fanny Demars  |   Alain Dervaux  |   Ariel Frajerman  |   Raphael Gaillard  |   Qin He  |   Anton Iftimovici  |   Thérèse Jay  |   Mathilde Kazes  |   Oussama Kebir  |   Gwenaëlle Le Pen  |   Gilles Martinez  |   Aude Marzo  |   Yannick Morvan  |   Anne Cécile Petit  |   Marion Plaze  |   Marco Pompili  |   Fabrice Rivollier  |   Alexandre Salvador  |   Fabien Vinckier  |   Dominique Willard

 

Psychiatric disorders result from complex interactions between genetic and/or developmental vulnerability and late environmental factors. Our previous results support a developmental form of schizophrenia (SCZ), in the continuum of autism spectrum disorders (ASD), and suggest that rare variants and developmental markers are useful for stratifying patients in order to propose personalized therapeutic strategies (Girard 2015, Gay 2013; Martinez 2017). We also identified, for the first time, dynamic epigenetic changes during psychosis onset, and provide new pathways to explore for disease-modifying strategies, namely oxidative stress regulation, axon guidance, and inflammatory pathways (Chan 2015 ; Kebir 2017). In addition, we identified Hipp/PFC connectivity as a hub for modeling stress disorders (anxiety, depression), psychosis, and SCZ, and provide new means for identifying therapeutic targets (Godsil, 2015 ; Magalhães 2017, Rame 2016).

Our project aims at deciphering the processes underlying the onset and outcome of psychotic disorders, taking into account the developmental and/or genetic background. We will follow a reversible translational strategy in humans and in rodent models (i) at the molecular level (biomarkers, epigenetic regulation) and cellular level, by using a novel in vitro model, developed with A Hosmalin (Institut Cochin), that provides monocyte-derived-neuronal-like-cells (MDN) from peripheral blood; (ii) at the system level (imaging, cognitive models) focusing on hippocampo-prefrontal (HpPf) networks.

These studies should help identifying new personalized and preventive therapeutic strategies in early stages of schizophrenia spectrum disorders.

 

5 main publications

Frajerman A,  Morvan Y,  Krebs MO, Gorwood P, Chaumette B:Burnout in medical students before residency: A systematic review and meta-analysis. European Psychiatry

 

Kebir O* Chaumette B*, Rivollier F, Miozzo F, Lemieux Perreault LP, Barhdadi A, Provost S, Plaze M, Bourgin J, the ICAAR team, Gaillard R, Mezger V, Dube MP, Krebs MO : Methylomic changes during conversion to psychosis Mol Psychiatry, 2017 22:512-518.


Magalhães R, Barrière DA, Novais A, Marques F, Marques P, Cerqueira J, Sousa JC, Cachia A, Boumezbeur F, Bottlaender M, Jay TM, Mériaux S, Sousa N. The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome. Mol Psychiatry. 2017 Dec 5. doi: 10.1038/mp.2017.244.


Renard J, Vitalis T, Rame M, Krebs MO, Lenkei Z, Le Pen G, Jay TM. Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex. Eur Neuropsychopharmacol. 2016 Jan;26(1):55-64.


Vinckier F, Gaillard R, Palminteri S, Rigoux L, Salvador A, Fornito A, Adapa R, Krebs MO, Pessiglione M, Fletcher PC. Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade. Mol Psychiatry. 2016 Jul;21(7):946-55.


Gay O, Plaze M, Oppenheim C, Mouchet-Mages S, Gaillard R, Olié JP, Krebs MO, Cachia A. Cortex Morphology in First-Episode Psychosis Patients With Neurological Soft Signs. Schizophrenia Bull 2013 Jul;39(4):820-9.

 



The team’s projects aim to:



•    improve subgrouping of severe psychiatric disorders by focusing on the developmental anomalies and on treatment resistant disorders
•    identify early biomarkers and predictors of outcomes
•    explore the influence of environmental precipitating (stress, fear, substance use, aging) and protective factors (cognitive training) on vulnerable conditions
•    explore the neural and cognitive basis of specific dimensions in order to propose specific therapeutics.



Thanks to our in-house expertise and established collaborations we are using and developing:



•    multi-modal objective phenotyping (clinical and cognitive profiling, neurophysiological, sensorimotor and oculomotor exploration, and brain imaging explorations)
•    cutting edge whole genome molecular approaches exploring genetic, epigenetic and proteomic
•    bioinformatics analyses to address the challenge of heterogeneous large-scale data integration
•    in vivo rodents models to explore the neural underpinnings of psychiatric conditions with behavioral analysis coupled to:
                         ►   optogenetics
                         ►   multichannel electrophysiology
                         ►   pharmacology
•    in-vitro cellular models such as monocytes derived neuron-like cells and computational models to characterize pharmacological modulation
•    new cognitive exploration and remediation programs

The team comprises 7 PIs and 37 other researchers such as PhD students, post-docs, research assistants, and clinicians that are dedicated to research only part-time.
Our research develops around four main axes shaping also four subdivisions of the team:

 

1)    Disentangling early developmental alterations from adult psychosis


 

Team members

Prof Marie-Odile KREBS, MD, PhD

Professor of Psychiatry

Dr Alain DERVAUX, MD PhD

Psychiatrist and Clinical researcher

Dr Pauline CHASTE, MD PhD

Psychiatrist and Clinical researcher

Dr Gwenaelle LE PEN, PhD

Olivier GAY, MD

Researcher (CR1 INSERM)

Head resident and PhD student

Dr Gilles MARTINEZ, MD

Head resident and PhD student  

Dr Macarena CUENCA, MD

Psychiatrist and Clinical researcher

Me Charlotte ALEXANDRE

Psychologist, PhD student

Selected recent publications:

Alexandre C, Chaumette B, Martinez G, Christa L, Dupont J.M., Kebir O, Gaillard R, Amado I, Krebs M.O. (2015) Paradoxical improvement of schizoprenic symptoms by a dopaminergic agonist : an example of personalized psychiatry in a CNV carrying patient. Biol Psychiatry, S0006-3223(15)00813-6
 

Kebir O, Chaumette B, Fatjó-Vilas M, Ambalavanan A, Ramoz N, Xiong L, Mouaffak F, Millet B, Jaafari N, DeLisi LE, Levinson D, Joober R, Fañanás L, Rouleau G, Dubertret C, Krebs MO (2014) Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia. Schizophr Res. 160(1-3):97-103.
 

Cachia A, Amad A, Brunelin J, Krebs MO, Plaze M, Thomas P, Jardri R. (2015) Deviations in cortex sulcation associated with visual hallucinations in schizophrenia. Mol Psychiatry  20(9):1101-7.
 

Gay O, Plaze M, Oppenheim C, Mouchet-Mages S, Gaillard R, Olié JP, Krebs MO, Cachia A (2013) Cortex Morphology in First-Episode Psychosis Patients With Neurological Soft Signs. Schizophrenia Bull 39(4):820-9.
 

Girard S, Gauthier J, Noreau N, Xiong L, Zhou S, Jouan L, Dionne-Laporte A, Spiegelman D, Henrion E, Diallo O, Thibodeau P, Bachand I, Bao JYJ, Tong AMY, Lin CH, Millet B, Jaafari N, Joober R, Dion PA, Lok Si, Krebs MO, Rouleau GA (2011) Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 43(9):860-3.
 

Le Pen G, Jay TM and Krebs MO (2011) Effect of antipsychotics on spontaneous hyperactivity and hypersensitivity to mk-801-induced hyperactivity in rats prenatally exposed to methylazoxymethanol. J Psychopharmacol. 25(6):822-35.
 

Tarabeux J¬, Champagne N, Brustein E, Hamdan FF, Julie Gauthier J , Lapointe M, Maios C,    Piton A, Spiegelman D, Henrion E, S2D team, Millet B, Rapoport JL, DeLisi LE, Joober R, Fathalli F, Fombonne E, Mottron L, Forget-Dubois N, Boivin M, Michaud JL, Lafrenière RG, Drapeau P, Krebs MO, Rouleau GA. (2010) De Novo Truncating Mutation in KIF17 Associated with Schizophrenia. Biol Psychiatry 68(7):649-56.

 

2)    Exploring the neural basis of symptoms to personalize therapeutic strategies

 

Team members

Prof Raphaël GAILLARD, MD PhD

Professor of Psychiatry

Dr Isabelle AMADO, MD PhD

Psychiatrist and clinical researcher

Dr Marion PLAZE, MD PhD

Psychiatrist and clinical researcher

Dr Pierre DE MARICOURT, MD

Dr Catherine DOYEN, MD

Psychiatrist and clinical researcher

Psychiatrist and clinical researcher

Dr Thierry GALLARDA, MD

Psychiatrist and clinical researcher

Mrs Simona CALDANI

Psychologist, PhD student

Dr Rita Dadi, MD

Psychiatrist and clinical researcher

Mrs Célia MAM LAM FOOK

Psychologist, PhD student

Dr Alexandre SALVADOR, MD

Head resident, PhD student

Dr Sarah SMADJA, MD

Head resident, PhD student

Dr Fabien VINCKIER, MD PhD

Head resident and clinical researcher

Dr Eirini RARI, PhD

 

Psychologistand clinical researcher

Selected recent
publications:

Plaze M, Mangin JF, Paillère-Martinot ML, Artiges E, Olié JP, Krebs MO, Gaillard R, Martinot JL, Cachia A. "Who is talking to me?" - Self-other attribution of auditory hallucinations and sulcation of the right temporoparietal junction. Schizophr Res. 2015 Oct 10. pii: S0920-9964(15)30011-6. doi: 10.1016/j.schres.2015.10.011 [in press]
 

Vinckier F, Gaillard R, Palminteri S, Rigoux L, Salvador A, Fornito A, Adapa R, Krebs MO, Pessiglione M, Fletcher PC. Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.  Mol Psychiatry. 2015 Jun 9. doi: 10.1038/mp.2015.73. [Epub ahead of print]
 

Vinckier F, Cohen L, Oppenheim C, Salvador A, Picard H, Amado I, Krebs MO, Gaillard R. Reading impairment in schizophrenia: Dysconnectivity within the visual system. Neuropsychologia. 2014 Jan;53:187-96.

 

Sperduti M, Martinelli P, Kalenzaga S, Devauchelle AD, Lion S, Malherbe C, Gallarda T, Amado I, Krebs MO, Oppenheim C, Piolino P. Don't be Too Strict with Yourself! Rigid Negative Self-Representation in Healthy Subjects Mimics the Neurocognitive Profile of Depression for Autobiographical Memory. Front Behav Neurosci. 2013 May 21;7:41.
 

Landgraf S, Amado I, Brucks M, Krueger F, Krebs MO, van der Meer E. Inflexible information acquisition strategies mediate visuo-spatial reasoning in stabilized schizophrenia patients. World J Biol Psychiatry. 2011 Dec;12(8):608-19.

 

3)      Gene-environment interactions: epigenetic and rare variants

 

Team members

Dr Oussama KEBIR, MD PhD

Psychiatrist and clinical researcher

Dr Boris CHAUMETTE, MD

Resident and PhD student

Dr Julie ROBLIN, MD

Psychiatrist and clinical researcher

Dr Nicolas BAUP, MD PhD

Psychiatrist and clinical researcher

Dr Claire GAUTHIER, MD

Head resident clinical researcher

Dr Fabrice RIVOLLIER, MD

Psychiatrist and clinical researcher  

Selected recent publications:

Millan MJ, Andrieux A, Bartzokis G, Cadenhead K, Dazzan P, Fusar-Poli P, Gallinat J, Giedd J, Grayson D, Heinrichs M, Kahn R, Krebs MO, Leboyer M, Lewis D, Marin O, Marin P, Meyer-Lindenberg A, McGorry P, McGuire P, Owen MJ, Patterson P, Sawa A, Spedding M, Uhlhaas P, Vaccarino F, Wahlestedt C and Weinberger D : Altering the course of schizophrenia:  progress and perspectives, Nat Rev Drug Disc, in press.
 

Kebir O, Chaumette B, Fatjó-Vilas M, Ambalavanan A, Ramoz N, Xiong L, Mouaffak F, Millet B, Jaafari N, DeLisi LE, Levinson D, Joober R, Fañanás L, Rouleau G, Dubertret C, Krebs MO. Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia. Schizophr Res. 2014 Dec;160(1-3):97-103.
 

European Network of National Networks studying Gene-Environment Interactions in Schizophrenia (EU-GEI), van Os J, et al. Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations. Schizophr Bull. 2014 Jul;40(4):729-36.


4)      Lifetime perspective of neuroplasticity: critical periods and the stress response

 

Team members

Dr Thérèse JAY, PhD

Research director (group coordinator)

Dr Gwenaëlle LE PEN, PhD

Researcher (CR1 INSERM)

Dr Julie BOURGIN, MD PhD

Psychiatrist and clinical researcher

Dr Mathilde KAZES, MD PhD

Psychiatrist

Dr David BARRIERE, PhD

Post-doc

Dr Claire DABAN, PhD

Psychologist

Mr Adam Eckmier

PhD student

Mr Marco POMPILI

PhD student

Mrs Clémentine VINCENT

PhD student

Mrs Alice OPPETIT

Resident and MSc student

Mrs Mélanie CHAYET

Psychologist

Mr Zbigniew ZIELINSKI

Research assistant

Selected recent publications:

Renard J, Vitalis T, Rame M, Krebs MO, Lenkei Z, Le Pen G, Jay TM (2015) Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex. Eur Neuropsychopharmacol. S0924-977X(15)00355-7
 

Chaumette, B., Kebir, O., Mam-Lam-Fook, C., Morvan, Y., Bourgin, J., Godsil, B.P., Plaze M., Gaillard, R., Jay, T. M., Krebs, MO (2015) Salivary cortisol in early psychosis: new findings and meta-analysis. Psychoneuroendocrinology 63:262-270
 

Bourgin J, Cachia A, Boumezbeur F, Djemaï B, Bottlaender M, Duchesnay E, Mériaux S, Jay TM (2015) Hyper-responsivity to stress in rats is associated with a large increase in amygdala volume. A 7T MRI study. Eur Neuropsychopharmacol 25(6):828-35
 

Godsil BP, Bontempi B, Mailliet F, Delagrange P, Spedding M, Jay TM (2015) Acute tianeptine treatment selectively modulates neuronal activation in the central nucleus of the amygdala and attenuates fear extinction. Mol Psychiatry  20: 1420-1427
 

Godsil BP, Kiss JP, Spedding M, Jay TM (2013) The hippocampal prefrontal pathway: the link in psychiatric disorders? Eur Neuropsychopharmacol 23(10):1165-81