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A reverse translational study of redox dysregulation in psychiatric disorders: role of oxidative stress in functional and structural dysconnectivity during neurodevelopment

English title A reverse translational study of redox dysregulation in psychiatric disorders: role of oxidative stress in functional and structural dysconnectivity during neurodevelopment
Applicant Do Cuenod Kim
Number 135736
Funding scheme Project funding (Div. I-III)
Research institution Centre de neurosciences psychiatriques Département de Psychiatrie CHUV
Institution of higher education University of Lausanne - LA
Main discipline Neurophysiology and Brain Research
Start/End 01.06.2011 - 31.05.2014
Approved amount 346'393.00
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All Disciplines (3)

Discipline
Neurophysiology and Brain Research
Neurology, Psychiatry
Pathophysiology

Keywords (9)

Schizophrenia; Bipolar disorder; Oxidative stress; Glutathione; Fast spiking parvalbumine ; Interneurons; Perineuronal net; Connectivity; Myelin

Lay Summary (French)

Lead
Lay summary

Dérégulation de la balance réductions/oxydations dans les troubles psychiatriques: rôle du stress oxydatif au cours du développement dans les anomalies de la connectivité

 

Ce projet vise une meilleure compréhension des relations entre différentes psychoses et des facteurs externes susceptibles de les influencer, ouvrant la voie à des interventions prophylactiques au moment le plus favorable. De plus, la mise en évidence des mécanismes responsables des anomalies de connections pourront conduire à de nouveaux traitements. Les perspectives économiques sont importantes quand on considère qu’en addition aux souffrances individuelles et familiales, la schizophrénie à elle seule coûte 3 à 4 milliards à la Suisse en frais de santé et d’invalidité.

 

L'équilibre entre états de réduction et d'oxydation (redox) jour un rôle déterminant dans le développement du cerveau. Une dérégulation d'origine génétique de la balance redox entraîne des stress oxydatifs lorsqu'elle est combinée avec divers impacts environnementaux tels qu'infections prénatales, complications à la naissance ou traumatismes psycho-sociaux majeurs. Une telle dérégulation peut être due à une anomalie de la synthèse du glutathion, une molécule essentielle au maintien de l'équilibre redox. Nous avons montré que la synthèse du glutathion est perturbée chez certains patients souffrant de schizphrénie. Le but de cette recherche est d'étudier dans un modèle animal déficient en glutathion (gclm-/-) par quels mécanismes cette dérégulation entraîne les troubles du système nerveux caractéristiques de la maladie. En effet, le cerveau des patients présente des anomalies de certains neurones inhibiteurs dans le cortex frontal et temporal ("micro-circuits") ainsi que des connections reliant diverses régions du cerveau ("macro-circuits"). Ces mêmes anomalies aux mêmes endroits sont observées dans l'animal gclm-/-, permettant d'analyser les mécanismes par lesquels le stress oxydatif induit ces anomalies et de tenter de les corriger, afin de mieux traiter la maladie.  

 

Par ailleurs, de nombreuses observations suggèrent que d’autres affections psychiatriques, telles que les troubles bipolaires, dits maniaco-dépressifs, pourraient également trouver leur origine dans un déséquilibre redox. Nous proposons donc de tester l’hypothèse suivante: Le système nerveux se développe par étapes, les structures responsables des diverses fonctions se mettant successivement en place. Dans un organisme dont la synthèse du glutathion est déficiente, le moment de l’intervention d’impacts pathogènes environnementaux, causes de stress oxydatif, pourraient avoir des effets différents, suivant l’état développemental des structures cérébrales à ces différents temps, entraînant des insuffisances correspondantes et conduisant à des tableaux cliniques variés.

 

Dans la souris gclm-/-, nous proposons donc d’étudier l’effet de stress appliqués à différents moments du développement sur les micro- et les macro-circuits. En particulier, de voir s’ils causent des déficits dans des systèmes fonctionnels différents, impliqués dans les activités soit cognitives, soit affectives. Nous visons également une meilleure compréhension des mécanismes moléculaires et cellulaires conduisant à ces anomalies, dans le but de les prévenir.

 

 

Keywords: schizophrenia, bipolar disease, reductions/oxidations, glutathione, brain development, health costs, animal model, psycho-social stress

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Decreased brain levels of vitamin B12 in aging, autism and schizophrenia
Zhang Y, Hodgson NW, Trivedi MS, Abdolmaleky HM, Fournier M, Cuenod M, Do KQ, Deth RC (2016), Decreased brain levels of vitamin B12 in aging, autism and schizophrenia, in PloS One, 11(1), e0146797.
Glutamate cysteine ligase-modulatory subunit knockout mouse shows normal insulin sensitivity but reduced liver glycogen storage
Lavoie S, Steullet P, Kulak A, Preitner F, Do KQ, Magistretti PJ (2016), Glutamate cysteine ligase-modulatory subunit knockout mouse shows normal insulin sensitivity but reduced liver glycogen storage, in Frontiers in Physiology , 7, 142.
Glutathione deficit affects the integrity and function of the fimbria/fornix and anterior commissure in mice: relevance for schizophrenia
Corcoba A, Steullet P, Duarte JMN, Van de LooijY, Monin A, Cuenod M, Gruetter R, Do KQ (2016), Glutathione deficit affects the integrity and function of the fimbria/fornix and anterior commissure in mice: relevance for schizophrenia, in International Journal of Neuropsychopharmacology, 19(3), 1-11.
Linking early-life NMDAR hypo function and oxidative stress in schizophrenia pathogenesis
Hardingham GE, Do KQ (2016), Linking early-life NMDAR hypo function and oxidative stress in schizophrenia pathogenesis, in Nature Reviews Neuroscience, 17(2), 125-134.
Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: a “central hub” in schizophrenia pathophysiology?
Steullet P, Cabungcal JH, Monin A, Dwir D, O'Donnell P, Cuenod M, Do KQ (2016), Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: a “central hub” in schizophrenia pathophysiology?, in Schizophrenia Research, 176 (1), 41-51.
Adolescent social stress and oxidative stress in animal models
O'Donnell P, Lanz T, Do KQ (2015), Adolescent social stress and oxidative stress in animal models, in Biological Psychiatry, 77(9S), 28S.
Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin
Rossier J, Bernard A, Cabungcal JH, Perrenoud Q, Savoye A, Gallopin T, Hawrylycz M, Cuenod M, Do KQ, Urban A, Lein Ed S (2015), Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin, in Molecular Psychiatry, 20(2), 154-161.
Evidence from imaging studies for oxidative stress mechanisms in first episode schizophrenia
Do KQ, Alameda L, Baumann PS, Cabungcal JH, Corcoba A, Duarte JM, Ferrari C, Fournier M, Griffa A, Monin A, Steullet P, Van de Looij Y, Xin L, Cuenod M, Gruetter R, Thiran JP, Hagmann P, Conus P (2015), Evidence from imaging studies for oxidative stress mechanisms in first episode schizophrenia, in Schizophrenia Bulletin, 41(Suppl.1), S253.
Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients
Monin A, Baumann PS, Griffa A, Xin L, Mekle R, Fournier M, Butticaz C, Klaey M, Cabungcal JH, Steullet P, Ferrari C, Cuenod M, Gruetter R, Thiran JP, Hagmann P, Conus P, Do KQ (2015), Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients, in Molecular Psychiatry, 20(7), 827-838.
Inflammation in schizophrenia: a question of balance
Leza JC, Bueno BG, Bioque M, Arango C, Parellada M, Do KQ, O'Donnell P, Bernardo M (2015), Inflammation in schizophrenia: a question of balance, in Neuroscience and Biobehavioral Reviews, 55, 612-626.
Oxidative stress: biomarkers guided treatment and prevention in psychosis
Do KQ, Cuenod M, O'Donnell P (2015), Oxidative stress: biomarkers guided treatment and prevention in psychosis, in Schizophrenia Bulletin, 41(Suppl.1), S285.
Presymptomatic antioxidants prevent adult deficits in a developmental rodent model of schizophrenia
O'Donnell P, Do KQ (2015), Presymptomatic antioxidants prevent adult deficits in a developmental rodent model of schizophrenia, in Schizophrenia Bulletin, 41(Suppl.1), S35.
Prolonged period of cortical plasticity upon redox dysregulation in fast-spiking interneurons
Morishita H, Cabungcal JH, Chen Y, Do KQ, Hensch TK (2015), Prolonged period of cortical plasticity upon redox dysregulation in fast-spiking interneurons, in Biological Psychiatry, 78(6), 396-402.
Receptor for advanced glycation end-product (RAGE) as linking mechanism between neuroinflammation and oxidative stress
Do KQ, Dwir D, Cabungcal JH, Tirouvanziam R, Cuenod M (2015), Receptor for advanced glycation end-product (RAGE) as linking mechanism between neuroinflammation and oxidative stress, in Schizophrenia Bulletin, 41(Suppl.1), S2.
Role of redox dysregulation in white matter anomalies associated with schizophrenia
Monin A, Fournier M, Baumann PS, Cuenod M, Do KQ (2015), Role of redox dysregulation in white matter anomalies associated with schizophrenia, in Pletnikov Mikhail V & Waddington John L (ed.), Elsevier, Amsterdam, 481-500.
Targeting oxidative stress and aberrant critical period plasticity in the developmental trajectory to schizophrenia
Do KQ, Cuenod M, Hensch TK (2015), Targeting oxidative stress and aberrant critical period plasticity in the developmental trajectory to schizophrenia, in Schizophrenia Bulletin, 41(4), 835-846.
Defect of the Perineuronal Nets Enwrapping Parvalbumin Interneurons in a Mouse Model of Schizophrenia can be Prevented by N-acetylcysteine
Cabungcal Jan-Harry, et al. (2014), Defect of the Perineuronal Nets Enwrapping Parvalbumin Interneurons in a Mouse Model of Schizophrenia can be Prevented by N-acetylcysteine, in Biological Psychiatry, 75(9S), 176S.
Evaluation of Redox Dysregulation in the Pathology of Schizophrenia Using Induced Pluripotent Stem Cell Technology
Giangreco Basilio, et al. (2014), Evaluation of Redox Dysregulation in the Pathology of Schizophrenia Using Induced Pluripotent Stem Cell Technology, in Biological Psychiatry, 75(9S), 186S.
Fast oscillatory activity in the anterior cingular cortex: dopaminergic modulation and effect of perineuronal net loss
Steullet P, Cabungcal JH, Cuenod M, Do KQ (2014), Fast oscillatory activity in the anterior cingular cortex: dopaminergic modulation and effect of perineuronal net loss, in Frontiers in Cellular Neuroscience, 00244.
Genetic Association with Prefrontal Glutathione Deficit: a 3T 1H MRS Study in Early Psychosis
Xin. Lijing, et al. (2014), Genetic Association with Prefrontal Glutathione Deficit: a 3T 1H MRS Study in Early Psychosis, in Biological Psychiatry, 75(9S), 108S.
Glutathione Deficit Affects White Matter Integrity in Prefrontal Cortex and Impairs Brain Connectivity in Schizophrenia
Monin Aline, et al. (2014), Glutathione Deficit Affects White Matter Integrity in Prefrontal Cortex and Impairs Brain Connectivity in Schizophrenia, in Biological Psychiatry, 75(9S), 185S.
Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients
Fournier Margot, et al. (2014), Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients, in Biological Psychiatry, 75(9S), 272S.
Impaired White Matter Integrity in Fornix and Anterior Commissure in a Schizophrenia Mouse Model of Redox Dysregulation
Corcoba Alberto, et al. (2014), Impaired White Matter Integrity in Fornix and Anterior Commissure in a Schizophrenia Mouse Model of Redox Dysregulation, in Biological Psychiatry, 75(9S), 175S.
Integrity of the fornix and hippocampus and relationship with peripheral oxidative stress markers in early phase psychosis
Baumann Philipp S., et al. (2014), Integrity of the fornix and hippocampus and relationship with peripheral oxidative stress markers in early phase psychosis, in Biological Psychiatry, 75(9S), 109s.
Involvement of the Receptor for Advanced Glycation End-product (RAGE) in Redox Dysregulation and Neuroinflammation in an Animal Model of Schizophrenia
Dwir Daniella, et al. (2014), Involvement of the Receptor for Advanced Glycation End-product (RAGE) in Redox Dysregulation and Neuroinflammation in an Animal Model of Schizophrenia, in Biological Psychiatry, 75(9S), 185S.
Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia
Cabungcal JH, Counotte DS, Lewis E, Tejeda HA, Piantadosi P, Pollock C, Calhoon GG, Sullivan E, Presgraves E, Kil JJ, Hong LE, Cuenod M, Do KQ, O'Donnell P (2014), Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia, in Neuron, 83(5), 1073-1084.
Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by (1)H magnetic resonance spectroscopy
Duarte JM, Do KQ, Gruetter R (2014), Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by (1)H magnetic resonance spectroscopy, in Neurobiology of Aging, 35(7), 1660-1668.
Oxidative/nitrostative stress in psychiatric disorders: are we there yet?
O'Donnell P, Do KQ, Arango C (2014), Oxidative/nitrostative stress in psychiatric disorders: are we there yet?, in Schizophrenia Bulletin, 40(5), 960-962.
Sexual and Physical Trauma and the Social and Vocational Functioning in First-episode Psychosis Patients
Alameda Luis, et al. (2014), Sexual and Physical Trauma and the Social and Vocational Functioning in First-episode Psychosis Patients, in Biological Psychiatry, 75(9S), 342S.
Early-life insults impair parvalbumin interneurons via oxidative stress
Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ (2013), Early-life insults impair parvalbumin interneurons via oxidative stress, in Biological Psychiatry, 73(6), 574-582.
Gènes, environnement et neurodéveloppement: le cas de la schizophrénie
Do Kim Q. (2013), Gènes, environnement et neurodéveloppement: le cas de la schizophrénie, in Revue Médicale Suisse, 9, 1672-1677.
Perineuronal nets protect fast-spiking interneurons against oxidative stress
Cabungcal JH, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK, Do KQ (2013), Perineuronal nets protect fast-spiking interneurons against oxidative stress, in Proceedings of the National Academy of Sciences USA, 110(22), 9130-9135.
Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models
Kulak A, Steullet P, Cabungcal JH, Werge T, Ingason A, Cuenod M, Do KQ (2013), Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models, in Antioxidants & Redox Signaling, 18(12), 1428-1443.
Treatment and early intervention in psychosis program (TIPP-Lausanne): implementation of an early intervention programme for psychosis in Switzerland
Baumann PS, Crespi S, Marion-Veyron R, Solida A, Thonney J, Favrod J, Bonsack C, Do KQ, Conus P (2013), Treatment and early intervention in psychosis program (TIPP-Lausanne): implementation of an early intervention programme for psychosis in Switzerland, in Early Intervention in Psychiatry, 7(3), 322-328.
Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder
Kulak A, Cuenod M, Do KQ (2012), Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder, in Behavioural Brain Research, 226(2), 563-570.
Glutathione Deficit and Xct in Schizophrenia: Modulation of Neurochemical Profile by N-Acetylcysteine in Mouse Model
Do KQ (2012), Glutathione Deficit and Xct in Schizophrenia: Modulation of Neurochemical Profile by N-Acetylcysteine in Mouse Model, in Biological Psychiatry, 71(8), 270S.
Glutathione deficit in animal models of schizophrenia
Steullet P, Cabungcal JH, Kulak A, Cuenod M, Schenk F, Do KQ (2012), Glutathione deficit in animal models of schizophrenia, in P. O’Donnell (ed.), Humana Press, New York, 149-188.
Glutathione precursor, N-acetyl-cysteine, modulates EEG synchronization in schizophrenia patients: a double-blind randomized placebo-controlled trial
Carmeli C, Knyazeva MG, Cuenod M, Do KQ (2012), Glutathione precursor, N-acetyl-cysteine, modulates EEG synchronization in schizophrenia patients: a double-blind randomized placebo-controlled trial, in PLoS ONE, 7(2), e29341-00.
High b-value diffusion-weighted imaging: A sensitive method to reveal white matter differences in schizophrenia
Baumann PS, Cammoun L, Conus P, Do KQ, Marquet P, Meskaldji D, Meuli R, Thiran JP, Hagmann P (2012), High b-value diffusion-weighted imaging: A sensitive method to reveal white matter differences in schizophrenia, in Psychiatry Research: Neuroimaging, 201(2), 144-151.
Investigating the joined effects of genetically compromized antioxidant system and peripubertal stress on stress hormone levels and behavior in mice
Kulak A, Marquez C, Sandi C, et al. (2012), Investigating the joined effects of genetically compromized antioxidant system and peripubertal stress on stress hormone levels and behavior in mice, in Biological Psychiatry, 71(8), 39S.
Investigation of network metrics correlation with frontal glutathione levels in control and first episode psychosis subjects
Griffa A, Baumann PS, Xin L, et al. (2012), Investigation of network metrics correlation with frontal glutathione levels in control and first episode psychosis subjects, in Biological Psychiatry, 71(8), 254S.
Mapping the human connectome at multiple scales with diffusion spectrum MRI
Cammoun L, Gigandet X, Meskaldji D, Thiran JP, Sporns O, Do KQ, Maeder P, Meuli R, Hagmann P (2012), Mapping the human connectome at multiple scales with diffusion spectrum MRI, in Journal of Neuroscience Methods, 203(2), 386-397.
MRS frontal glutathione levels correlate with DSI white matter integrity measure in control subjects but not in early psychosis patients
Baumann PS, Griffa A, Xin L, et al. (2012), MRS frontal glutathione levels correlate with DSI white matter integrity measure in control subjects but not in early psychosis patients, in Biological Psychiatry, 71(8), 259S.
N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development
Duarte JMN, Kulak A, Gholam-Razaee MM, Cuenod M, Gruetter R, Do KQ (2012), N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development, in Biological Psychiatry, 71(11), 1006-1014.
Redox dysregulation affects proliferation, differentiation of oligodendrocytes progenitors and myelination: relevance to dysconnectivity in schizophrenia
Do KQ, Monin A, Klaey M, Butticaz C, Cabungcal JH, Steullet P, Cuenod M (2012), Redox dysregulation affects proliferation, differentiation of oligodendrocytes progenitors and myelination: relevance to dysconnectivity in schizophrenia, in Biological Psychiatry, 71(8), 4S.
Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia
Lavoie S, Allaman I, Petit JM, Do KQ, Magistretti PJ (2011), Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia, in PLoS ONE, 6(7), e22875.
Genetic Dysregulation of Glutathione Synthesis Predicts Alteration of Plasma Thiol Redox Status in Schizophrenia
Gysin R, Kraftsik R, Boulat O, Bovet P, Conus P, Comte-Krieger E, Polari A, Steullet P, Preisig M, Teichmann T, Cuenod M, Do KQ (2011), Genetic Dysregulation of Glutathione Synthesis Predicts Alteration of Plasma Thiol Redox Status in Schizophrenia, in Antioxidants & Redox Signaling, 15(7), 2003-2010.
Interaction of GAG trinucleotide repeat and C-129T polymorphisms impairs expression of the glutamate-cysteine ligase catalytic subunit gene
Butticaz C, Gysin R, Cuenod M, Do KQ (2011), Interaction of GAG trinucleotide repeat and C-129T polymorphisms impairs expression of the glutamate-cysteine ligase catalytic subunit gene, in Free Radical Biology & Medicine, 50(5), 617-623.
Impaired metabolic reactivity to oxidative stress in early psychosis patients
Fournier M, Ferrari C, Baumann PS, Polari A, Monin A, Bellier-Teichmann T, Pappan K, Wulff J, Cuenod M, Conus P, Do KQ, Impaired metabolic reactivity to oxidative stress in early psychosis patients, in Schizophrenia Bulletin, Epub ahead of print.
Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression
Bouvier E, Brouillard F, Molet J, Claverie D, Cabungcal JH, Cresto N, Doligez N, Rivat C, Do KQ, Bernard C, Benoliel JJ, Becker C, Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression, in Molecular Psychiatry.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Plenary lecture, European College of Neuropsychopharmacology, 29th ECNP Congress Talk given at a conference Translational research in schizophrenia: towards therapy and prevention beyond dopamine antagonism 19.09.2016 Vienna, Austria Do Cuenod Kim;
39th Annual Meeting of the Japan Neuroscience Society Talk given at a conference Role of redox regulation in prefrontal parvalbumin interneurons and myelin maturation 22.07.2016 Yokohama, Japan Do Cuenod Kim;
Keynote lecture, Institute of Neuroscience, Chinese Academy of Sciences Individual talk Role of redox regulation, NMDA hypofunction and neuroinflammation in excitatory-inhibitory balance and myelin maturation in schizophrenia: a translational study 12.07.2016 Shanghai, China Do Cuenod Kim;
The International College of Neuropsychopharmacology, 30th CINP World Congress Talk given at a conference Interaction between oxidative stress and neuroinflammation during early development in schizophrenia: role of RAGE and metalloproteases 05.07.2016 Seoul, Korean Republic (South Korea) Do Cuenod Kim;
Brain Mind Symposium, Brain bioenergetics - From behavior to pathology Talk given at a conference Redox dysregulation in schizophrenia: implication of high energy metabolism nerve cells 29.06.2016 Lausanne, Switzerland Do Cuenod Kim;
Plenary lecture, Neurogune 2016, Third Meeting of the Basque Research Community in Neuroscience Talk given at a conference Role of redox regulation and neuroinflammation in prefrontal excitatory-inhibitory balance and myelin maturation in schizophrenia: a human and mice study 07.06.2016 Bilbao, Spain Do Cuenod Kim;
Society of Biological Psychiatry, 71st Annual Scientific Convention and Program Talk given at a conference Convergence of various models on oxidative stress during development leading to parvalbumin-interneurons impairments 12.05.2016 Atlanta, United States of America Do Cuenod Kim;
Keynote lecture, University of Glasgow School of Medicine, Institute of Neuroscience & Psychology & Institute of Human Nutrition Individual talk Role of redox regulation and neuroinflammation in prefrontal excitatory-inhibitory balance and myelin maturation in schizophrenia 25.04.2016 Glasgow, Great Britain and Northern Ireland Do Cuenod Kim;
American College of Neuropsychopharmacology, 54th Annual Meeting Talk given at a conference Oxidative stress in interaction with NMDA receptor hypo function as a core mechanism in schizophrenia pathophysiology: spatial-temporal development and potential protection with antioxidants 09.12.2015 Hollywood, Florida, United States of America Do Cuenod Kim;
Société Suisse de psychiatrie et psychothérapie, Annual Meeting 2015 Talk given at a conference Towards stage-specific treatment and prevention of psychosis: a translational approach 04.09.2015 Bern, Switzerland Do Cuenod Kim;
Plenary Speaker, Swiss Society for Biological Psychiatry, 35th Annual Meeting Talk given at a conference Towards stage-specific treatment and prevention of psychosis: a translational approach 28.08.2015 Geneva, Switzerland Do Cuenod Kim;
EMBO Workshop, Cortical Interneurons in Health and Disease Talk given at a conference Vulnerability of parvalbumin interneurons to oxidative stress: implication in schizophrenia 23.06.2015 Mallorca, Spain Do Cuenod Kim;
15th International Congress on Schizophrenia Research Talk given at a conference Receptor for Advanced Glycation End-product (RAGE) as linking mechanism between neuroinflammation and oxidative stress 01.04.2015 Colorado Springs, United States of America Do Cuenod Kim;
15th International Congress on Schizophrenia Research Talk given at a conference Oxidative stress: biomarker guided treatment and prevention in psychosis 29.03.2015 Colorado Springs, United States of America Do Cuenod Kim;
Special Lecture, Neuroscience 2014, 44th Annual Meeting of the Society for Neuroscience Talk given at a conference Genes and environment interaction during development: redox imbalance in schizophrenia 17.11.2014 Washington DC, United States of America Do Cuenod Kim;
Keynote lecture, Central Institute of Mental Health, Department of Psychiatry Individual talk Oxidative stress, NMDA hypofunction and neuroinflammation in schizophrenia:a translational approach 07.10.2014 Mannheim, Germany Do Cuenod Kim;
Conference, Pfizer Inc., Neuroscience Research Unit, Psychiatry and Behavioral Disorders Individual talk Oxidative stress in psychosis: a translational approach towards new targets for specific treatment 13.05.2014 Cambridge, United States of America Do Cuenod Kim;
Conference, Harvard Medical School, Department of Psychiatry Individual talk Redox dysregulation in schizophrenia: functional anomalies prevented by N-acetyl-cysteine in translational models 12.05.2014 Boston, United States of America Do Cuenod Kim;
Society of Biological Psychiatry, 69th Annual Scientific Meeting Talk given at a conference Redox dysregulation affects myelination and parvalbumine interneurons in schizophrenia models 10.05.2014 New York, United States of America Do Cuenod Kim;
Society of Biological Psychiatry, 69th Annual Scientific Meeting Talk given at a conference Redox dysregulation models of schizophrenia: functional anomalies prevented by N-acetyl-cysteine 08.05.2014 New York, United States of America Do Cuenod Kim;
Conference, Kings College London, Institute of Psychiatry, Department of Psychosis Studies Individual talk Search for biomarkers and redox dysregulation in early psychosis: a translational approach 28.04.2014 London, Great Britain and Northern Ireland Do Cuenod Kim;
Swiss Society for Neuroscience, Annual Meeting Talk given at a conference Oxidative stress in psychosis: a translational approach 25.01.2014 Bern, Switzerland Do Cuenod Kim;
Lecture, PhD Course, Center for Biomedical Imaging, EPFL Individual talk Multimodal imaging in humans and animal models: towards early detection and novel drug targets in pychosis 13.12.2013 Lausanne, Switzerland Do Cuenod Kim;
2nd SFCNS Congress, Swiss Federation of Clinical Neuro-Societies Talk given at a conference Oxidative stress in psychosis: a translational approach 06.06.2013 Montreux, Switzerland Do Cuenod Kim;
Society of Biological Psychiatry, 68th Annual Scientific Meeting Talk given at a conference The perineuronal net protects fast-spiking parvalbumine interneurons against oxidative stress 18.05.2013 San Francisco, United States of America Do Cuenod Kim;
CINP Thematic Meeting, Pharmacogenomics and Personlised Medicine Talk given at a conference Redox imbalance in schizophrenia and its improvement by N-acetyl-cysteine 21.04.2013 Jerusalem, Israel Do Cuenod Kim;
Seminar, Institute of Anatomy and Cell Biology, Universita Cattolica del S. Cuore Individual talk Redox dysregulation in schizophrenia: a translational approach 05.04.2013 Rome, Italy Do Cuenod Kim;
The International College of Neuropsychopharmacology, 28th World Congress Talk given at a conference Oxidative stress and the development of mental disorders 05.06.2012 Stockholm, Sweden Do Cuenod Kim;
Seminar, Mount Sinai School of Medicine Individual talk Redox dysregulation, neurodevelopment and schizophrenia: a translational approach 07.05.2012 New York, United States of America Do Cuenod Kim;
Society of Biological Psychiatry, 67th Annual Scientific Convention and Program Talk given at a conference Connectomic abnormalities in schizophrenia 03.05.2012 Philadelphia, United States of America Do Cuenod Kim;
3rd Biennial Schizophrenia International Research Conference Talk given at a conference Role for oxidative stress, inflammation and misfolded protein in the early pathology of schizophrenia 16.04.2012 Florence, Italy Do Cuenod Kim;
Seminar, Collège de France Talk given at a conference Schizophrenia: gene and environment interactions of redox contro during development 16.03.2012 Paris, France Do Cuenod Kim;
Conference, Swiss Federal Institute of Technology Individual talk Schizophrenia and oxidative stress: toward new therapeutic targets 23.11.2011 Zurich, Switzerland Do Cuenod Kim;


Self-organised

Title Date Place

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Schizophrénie: la recherche progresse Western Switzerland 2016
Media relations: print media, online media La schizophrénie à l'échelle des neurones Largeur.com Western Switzerland 2015
Media relations: print media, online media Le CHUV et l'UNIL font avancer la recherche sur la schizophrénie RTS INFO Western Switzerland 2015
Media relations: print media, online media Le CHUV, l'UNIL et Harvard décryptent la schizophrénie Le Matin Western Switzerland 2015
Talks/events/exhibitions Où en est la recherche sur la schizophrénie? Western Switzerland 2015
New media (web, blogs, podcasts, news feeds etc.) Oxidative stress in schizophrenia: a translational approach Labroots Science Network International 2015
Media relations: print media, online media Proposition d'un mécanisme à la base de la schizophrénie Psychomédia International 2015
Talks/events/exhibitions Un pont entre sciences fondamentales et cliniques, une quête pour une cause: la schizophrénie Western Switzerland 2015
Talks/events/exhibitions Neurosciences et psychiatrie: le développement du cerveau, toutes les chances et tous les risques Western Switzerland 2014
Media relations: print media, online media Tuer la schizophrénie dans l'oeuf 24heures Western Switzerland 2014
New media (web, blogs, podcasts, news feeds etc.) 20Minutes online Des antioxydants pour prévenir la schizophrénie International 2013
Media relations: print media, online media Chercher pour aider les autres Horizons no 97 German-speaking Switzerland Western Switzerland 2013
Media relations: print media, online media CHUV: nouvelle cible thérapeutique contre la schizophrénie Agence Télégraphique Suisse Western Switzerland German-speaking Switzerland 2013
New media (web, blogs, podcasts, news feeds etc.) CHUV: une nouvelle cible thérapeutique contre la schizophrénie EPFL Actualités NCCR-Synapsy Western Switzerland 2013
New media (web, blogs, podcasts, news feeds etc.) Damaged Protective ‘Net’ May Cause Malfunction in Brain Cells in Schizophrenia http://bbrfoundation.org International 2013
New media (web, blogs, podcasts, news feeds etc.) N-acetylcysteine shows promise for schizophrenia www.lef.org International 2013
New media (web, blogs, podcasts, news feeds etc.) Neuron Loss in Schizophrenia and Depression Could Be Prevented With an Antioxidant www.elsevier.com International 2013
New media (web, blogs, podcasts, news feeds etc.) Neuron Loss in Schizophrenia and Depression Could Be Prevented, Study Suggests www.sciencedaily.com International 2013
Talks/events/exhibitions Neuroscience of the self in health and disease Western Switzerland 2013
New media (web, blogs, podcasts, news feeds etc.) Prévenir la schizophrénie chez les enfants EPFL Actualités NCCR-Synapsy Western Switzerland 2013
New media (web, blogs, podcasts, news feeds etc.) Safety Net: Perineuronal Nets Protect Interneurons Linked to Schizophrenia www.schizophreniaforum.org International 2013
Talks/events/exhibitions Schizophrénie: où en est la recherche? Western Switzerland 2013
Media relations: print media, online media Percer ensemble les secrets de la schizophrénie CHUV Magazine Western Switzerland 2012
Media relations: print media, online media Un antioxydant pour prévenir la schizophrénie Le Temps Western Switzerland 2012
Media relations: print media, online media Neurobiologie et schizophrénie: la piste du glutathion Diagonales - Magazine Romand de la Santé Mentale Western Switzerland 2011

Awards

Title Year
Biological Psychiatry - Honorable Mention for selection as a finalist for the 2014 Ziskind-Somerfeld Research Award 2014
Individual Member of the Swiss Academy of Medical Sciences 2014
SSN Travel Fellowship - Travel grant from the Swiss Society for Neuroscience 2013

Associated projects

Number Title Start Funding scheme
130090 Imaging the connectome in the early phase of psychosis 01.01.2011 Project funding (Div. I-III)
122419 Glutathion/redox dysregulation in early psychosis: towards a biomarker profile for early intervention 01.10.2008 Project funding (Div. I-III)
116689 Developmental animal model of schizophrenia: Redox dysregulation as susceptibility factor 01.07.2007 Project funding (Div. I-III)

Abstract

Background: Major psychiatric disorders appear to be due to the interaction between genetic vulnerability factors and various environmental impacts, particularly during development, but many aspects of the disease mechanisms are still unresolved. Converging evidence, including genetics, epidemiology, phenotypes and therapy, suggests that the spectrum of schizophrenia (SZ) and of bipolar disorder (BP) share, at least partially, some of these factors. One of the critical differences is the timing and intensity of insults during brain development, potentially leading to impairments of predominantly cognitive or affective functions if they are imposed respectively early or late. Oxidative stress markers are increased in SZ and BP. Results from our group significantly contribute to the hypothesis that redox dysregulation favoring oxidative stress constitutes a “hub” on which converge genetic and environmental factors. We demonstrated that an increase in oxidative stress can be due to a genetic dysfunction of glutathione (GSH) synthesis. Administration of N-acetylcysteine (NAC), an antioxidant and precursor of GSH, is beneficial to both SZ and BP patients. This new concept was tested in a “model animal” based on reverse translation, in which we showed that deletion of the modulatory subunit of GSH key synthesizing enzyme (gclm-/- mice) leads to phenotypes presenting impairments as observed in SZ and BP: The parvalbumin immunoreactivity of fast spiking interneurons (PVI) and their perineuronal net (PNN) in the anterior cingulate cortex (ACC) and in the ventral hippocampus are decreased, particularly following dopamine excess as stressor in young but not adult animals, an effect that can be prevented by NAC application. These defects correlate with anomalies of neuronal synchronization and of cognitive and affective behaviors. Aims: The global aim of this project is to gain information on the mechanisms underlying the similarities and the differences in SZ & BP, investigating, in a model animal carrying a genetic deficit closely related to the disease (gclm-/- mice), the effects of the timing and intensity of impacts during development on structural and functional networks involved in these pathologies. We also aim at better understanding the mechanisms controlling the development of prefrontal inhibitory interneurons and of myelin, in order to prevent their impairment by oxidative stress. Experimental design: We propose to investigate the contribution of early versus late insults in the gclm-/- mice model with a deficit of GSH synthesis. Variables: insults (GBR induced dopamine excess or psychosocial stress) and timing (perinatal, peri-pubertal, adult). Outputs: parameters implicated in the disease (PV, PNN, myelination, synchronization, behavior), determined in adulthood. We will investigate: • The brain distribution of oxidative stress damages (2.3.1.1) and their long-term consequences on behavior, particularly in cognitive and affective domains (2.3.1.2) in order to identify structural and functional constellations susceptible to be translated to human phenotypes. • In ACC, the long lasting effects of insults on PV and PNN (2.3.2.1a), on neuronal synchronization (2.3.2.2b) and on behavior (2.3.2.1c). • In ACC, the role of PNN as protection of PVI against the damaging effects of oxidative stress (2.3.2.2a) and the involvement of PNN in local neuronal synchronization (2.3.2.2b). • The role of the redox sensitive NMDAR subunit NR2A in PV maturation and PNN formation (2.3.2.2c). • The deleterious effect of developmental redox dysregulation on oligodendrocyte precursors proliferation and differentiation in vitro (2.3.3.1), on myelination in vivo (2.3.3.2) and on connectivity (DTI) (2.3.3.3), to assess the role of oxidative stress in white matter anomalies. Finally, if anomalies are observed, NAC will be administrated in attempt to prevent or reduce the deleterious effect of a redox dysregulation.Importance and impact: Results from the proposed projects will provide a better understanding of the underlying pathophysiological mechanisms at molecular, cellular and system levels. If the hypothesis is confirmed that the timing of insult tends to favor a cognitive or affective pole, it would support a unitary concept of psychoses and contribute to orient preventive measures. The identification of vulnerable brain structures, both at the cellular regional level (project A) and at the level of neural pathways (project C) and their potential correlation with complex behavioral impairments will be of great theoretical interest for anatomo-functional considerations. Understanding the role of the perineuronal net for the morphological and functional integrity of PVI when exposed to oxidative stress will help to develop new therapeutic targets (project B). Testing the reversal effect of NAC on this preclinical model will pave the way to novel preventive therapy devoid of side-effects. The projects are also of translational importance: The alignment of animal imaging data on structural connectivity and neurochemical profile (project C) with those on connectome and MRS collected in clinical studies presently underway in early psychosis patients will allow to discover non invasive biomarkers useful for early diagnosis and for monitoring the efficacy of new developed drugs.
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