Schizophrenia; Bipolar disorder; Oxidative stress; Glutathione; Fast spiking parvalbumine ; Interneurons; Perineuronal net; Connectivity; Myelin
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.
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.
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.
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.
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.
O'Donnell P, Lanz T, Do KQ (2015), Adolescent social stress and oxidative stress in animal models, in Biological Psychiatry
, 77(9S), 28S.
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.
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.
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.
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.
Do KQ, Cuenod M, O'Donnell P (2015), Oxidative stress: biomarkers guided treatment and prevention in psychosis, in Schizophrenia Bulletin
, 41(Suppl.1), S285.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
Fournier Margot, et al. (2014), Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients, in Biological Psychiatry
, 75(9S), 272S.
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.
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.
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.
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.
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.
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.
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.
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.
Do Kim Q. (2013), Gènes, environnement et neurodéveloppement: le cas de la schizophrénie, in Revue Médicale Suisse
, 9, 1672-1677.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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 (188.8.131.52) and their long-term consequences on behavior, particularly in cognitive and affective domains (184.108.40.206) 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 (220.127.116.11a), on neuronal synchronization (18.104.22.168b) and on behavior (22.214.171.124c). • In ACC, the role of PNN as protection of PVI against the damaging effects of oxidative stress (126.96.36.199a) and the involvement of PNN in local neuronal synchronization (188.8.131.52b). • The role of the redox sensitive NMDAR subunit NR2A in PV maturation and PNN formation (184.108.40.206c). • The deleterious effect of developmental redox dysregulation on oligodendrocyte precursors proliferation and differentiation in vitro (220.127.116.11), on myelination in vivo (18.104.22.168) and on connectivity (DTI) (22.214.171.124), 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.