unit for research in schizophrenia update 2013–2014

UNIT FOR RESEARCH IN SCHIZOPHRENIA
UPDATE
2013 – 2014
INTRODUCTION
The research program supported by the Alamaya Foundation focuses on a better understanding of
the causes and mechanisms of schizophrenia in order to identify biological markers for early
detection and intervention, and to develop preventive measures as well as new treatments.
The basic concept guiding our research can be summarized as follows: the anomalies in the brain of
patients involve on one hand a particular type of inhibitory neurons, called parvalbumin (PV)
interneurons, and, on the other hand, nervous fibers and their protective envelope, called myelin,
which connect the different parts of the central nervous system. These anomalies are responsible for
various manifestations of the disease, in particular for high frequency oscillations (EEG) and cognitive
disorders affecting memory, attention, concentration and action planning.
It is essential to discover the origin of these anomalies. Our hypothesis proposes that a deficient
control of oxidations in the human body (called "redox regulation") plays a central role in these
phenomena, the deficient control itself being caused by both genetic and environmental risk factors
during the development of the brain. Several genetic anomalies involved in schizophrenia lead to a
redox dysregulation and to oxidative stress. Environmental risk factors such infections,
inflammations, physical or psychological trauma also lead to oxidative stress. Furthermore, redox
dysregulation has a tight interaction with inflammatory immune reactions and the deficient
functioning of an excitatory receptor called "NMDAR". Thanks to our experimental models, we have
been able to validate our hypothesis to a large extent.
Figure illustrating several "hubs" on which
converge genetic and environmental risk factors
during the development of the brain, and which
lead to deficiencies of the excitatory/inhibitory
balance (E/I) in cortical microcircuits and in
macrocircuits, formed by fibers connecting the
various parts of the brain; these deficiencies are
responsible for the impairment of cognitive,
affective and social integration at the basis of
the disease symptoms.
1
PROGRESS AND RESULTS
The present evolution of clinical psychiatry in the field of schizophrenia is aimed at an early detection
of individuals who are at risk of the disease since experience shows that the prognosis is all the more
favorable if treatment begins early. It is therefore essential (a) to identify biological markers, which
are presently lacking, in order to be able to detect vulnerable persons; (b) to develop preventive
treatments devoid of serious side effects. These are two of the main objectives of the Unit for
Research in Schizophrenia (URS, Centre for Psychiatric Neuroscience, Lausanne University Hospital),
which strives to bridging clinical aspects with experimental research, and whose program has
reached significant international visibility and acknowledgement (see p. 7, Conclusion, video of the
American Psychiatric Association).
The URS develops following main working lines:
 Data collection in patients;
 Investigation of the disease mechanisms in experimental models;
 Exploration of biological markers and new potentially preventive treatments.
The translational approach of the URS has led to new discoveries in patients; among these are the
following:

MYELIN: Aline Monin (doctoral
student, URS) has studied the role of
redox regulation in oligodendrocyte
cultures; these are the cells
responsible for the formation of
myelin, which is essential to the
proper functioning of nervous fibres.
She has demonstrated that a
glutathione deficit causes a delay in
the maturation of oligodendrocytes,
and that myelin is deficient in the
prefrontal cortex of young mice with
a low level of glutathione. She has
also shown that this delay in the
formation of myelin is linked to the
excess of a particular enzyme, called "FYN kinase", probably due to the oxidation of
regulatory proteins.
Following this observation, Margot Fournier (post-doc, URS) has shown that FYN is also
increased in the cells of patients with a genetic anomaly hindering the formation of
glutathione. The FYN factor could thus be developed as a potential marker for the disease,
and pave the way for early intervention.
These results demonstrate the impact of oxidative stress on macrocircuits (see figure “Hubs
in schizophrenia”, p.1), namely on the integrity of nerve fibres which are essential for the
coordinated action of different brain regions. They thus confirm the role of oxidative stress
in the impairment of myelin, a key factor for the development of the disease, which could
be considered as a potential biomarker.
The results of this study have been published in Molecular Psychiatry, the scientific journal
with the highest impact factor in the field of psychiatry and neuroscience (see Annex I, press
release of the Lausanne University Hospital).
2

FORNIX: Alberto Corcoba (doctoral student, URS, in collaboration with Prof. R. Gruetter, CIBMEPFL) has developed a new, non-invasive and cutting-edge imaging method (MRI-DTI)
allowing the observation of the integrity of nervous fibres in the brain of glutathione
deficient mice; he recorded a reduced integrity in a nervous pathway originating in the
hippocampus, called the fornix, which is linked to the formation and consolidation of
memory.
This observation in the animal
model has prompted Philipp
Baumann
(clinician
and
researcher, URS & Service of
General
Psychiatry)
and
Alessandra Griffa (collaboration
with Dr P. Hagmann, Radiology,
Lausanne University Hospital, and
Dr J.-P. Thiran, Signal Processing
Laboratory 5, EPFL) to analyze –
with the same method – the
integrity of the fornix in patients
during their first psychotic
episode; as a result and for the
first time, they have revealed a
deficiency of this integrity (decreased gFA) in young patients. As explained below, the
investigations concerning a structure which is central to the functioning of memory are of
particular interest.

HIPPOCAMPUS: this brain structure plays an important role in the recording of memory; people
in whom this structure is defective have difficulties in consolidating their memories. In the
hippocampus of glutathione deficient mice, Pascal Steullet and Jan Cabungcal (senior
researchers, URS) have shown that PV cells and oscillations are deficient.
In patients, the volume of the
hippocampus is diminished, and
Philipp Baumann has demonstrated
that its decrease is proportionate to
the decrease of gFA in the fornix
(measure of the integrity of nervous
fibers). Furthermore, the volume of
the hippocampus is linked to a
blood
marker
of
redox
dysregulation: the higher the state
of oxidation, the smaller the
hippocampus. This represents a
direct evidence of the impact of
redox balance, measured in the
periphery, on a brain structure.
Finally and in parallel to these findings, recent data established by Luis Alameda (clinician and
researcher, URS & Service of General Psychiatry) show that patients who were subject to
traumatisms during adolescence have a smaller hippocampus. These observations have to be
correlated with those made in mice by Jan Cabungcal, indicating that an additional stress in
the young animal, and only in the young one, causes persistent anomalies of PV cells in the
frontal cortex.
This combination of results on the hippocampus complex and the fornix confirms the
important role of the redox balance in the development of these structures, which are
3
essential for key functions such as memory and the organization of space, and explain their
deficit in schizophrenia patients.

OTHER ANIMAL MODELS: Jan Cabungcal has studied the markers of oxidative stress in other
animal models of schizophrenia and other diseases, such as autism.
In collaboration with Patricio O’Donnell (University of Maryland, USA), he showed that a
neonatal lesion of the ventral hippocampus, a classical model of schizophrenia in rats, also
causes an oxidative stress in the prefrontal cortex.
As in mice with a genetically
induced low level of glutathione,
the
multiple
morphological,
physiological and behavioral
effects of this intervention can be
prevented by a treatment with Nacetyl-cysteine. This is all the
more interesting since the
intervention does not involve a
manipulation of the redox system
and clearly shows that diverse
impacts can converge on a redox
disturbance. Moreover, a model
of autism displays the same
oxidation characteristics as the glutathione deficient model of the URS.
These results suggest that a variety of pathological impacts could lead to oxidative stress,
which appears thus as a “core mechanism” or “common final path”, i.e. a site of
convergence of diverse causalities (see figure “Hubs in schizophrenia”, p.1). This concept
could lead to a new approach to the prevention of schizophrenia. Antioxidant drugs given
before overt clinical manifestations and at an early stage to people at risk may be able to
prevent the emergence of the disease.
The results of the study have been published in Neuron, a highly and internationally
renowned scientific journal (see Annexes II and III, press release of the Lausanne University
Hospital, and editorial of the Schizophrenia Research Forum Website). The article rose major
interest among the scientific and medical communities.
In a Neuron Previews Editorial, Prof. Akira Sawa (Department of Psychiatry, Johns Hopkins
University School of Medicine, Baltimore, USA) and Prof. Larry J. Seidman (Department of
Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA)
wrote an article entitled Is Prophylactic Psychiatry around the Corner? Combating
Adolescent Oxidative Stress for Adult Psychosis and Schizophrenia, which refers to the
study mentioned above. The mention of "prophylactic psychiatry" by these distinguished
scientists indicates that a major step forward has been achieved by the URS team as
regards the prevention of psychosis.
 IMMUNE REACTIONS: several data suggest that immune reactions and inflammation can play a
role in the development of schizophrenia. It is well-known that immune phenomena lead to
oxidative stress. We have explored the reverse possibility that redox dysregulation could
initiate immune reactions. Daniella Dwir (doctoral student, URS) has observed – in the
prefrontal cortex of glutathione deficient mice, thus exposed to oxidative stress – a
significant increase of activated immune "microglia" cells, which demonstrates the redox
influence on immune reactions. She showed that a factor called “RAGE” plays a critical role
in this interaction. Consistent with observations made in patients, these results show, in an
animal model, the close interaction between redox dysregulation and inflammation, and
4
demonstrate that they potentiate each other in a damaging positive feedback (see figure
“Hubs in schizophrenia”, p.1).
 METABOLOMICS: Margot Fournier has studied the effect of oxidative stress on the various
metabolites in the fibroblasts of patients. She observed that the reaction to stress of
different metabolic pathways is affected. As expected, the redox system is affected but also,
and these aspects are new, certain lipids, the arginine/nitric oxide system as well as the
extracellular matrix (protective envelope of nerve cells). These results have been published
in the journal Schizophrenia Bulletin.
The finding concerning the extracellular matrix is of particular interest since a specific form
of this matrix, called "perineuronal net", essential for the synaptic plasticity, is affected in
the brain of patients and in the animal model, as demonstrated by Jan Cabungcal and
Pascal Steullet (publication in the journal Proceedings of the National Academy of Sciences
USA in May 2013).
The multiple interactions described above suggest the existence of a scheme with several entries,
involving retroactive and combined effects of NMDAR hypofunction, inflammation and redox
dysregulation. It is probably by focusing on these three elements that preventive measures should be
envisioned (see figure “Hubs in schizophrenia, p.1).
A review article summarizing these results and their conceptual consequences has been prepared by
Pascal Steullet and published in Schizophrenia Research.
MAJOR INTERNATIONAL COLLABORATIONS
Scientists and researchers worldwide are interested in collaborating with Prof. Kim Do Cuénod and
her research group. Present collaborations include among others:

Harvard Medical School, Boston, USA, Department of Molecular & Cellular Biology, Prof.
Takao Hensch

Harvard Medical School, Boston, USA, Department of Psychiatry, Prof. Larry J. Seidman

University of Maryland School of Medicine, Baltimore, USA, Prof. Patricio O’Donnell

Mental Health Centre Sct. Hans, Capital Region of Denmark, Institute of Biological Psychiatry,
Prof. Thomas Werge
PUBLICATIONS 2013 – 2014
It has to be noted that Molecular Psychiatry and Neuron are two of the most influential and
selective scientific journals worldwide in the field of biological psychiatry and neuroscience.
Biological Psychiatry and Proceedings of the National Academy of Sciences USA also have a very high
impact factor.
The article published in Biological Psychiatry in 2013 has raised major interest among the
international scientific community as well as among the national and international media (see
Annexes IV, V VI).
5
ORIGINAL ARTICLES
Kulak A, Steullet P, Cabungcal JH, Werge T, Ingason A, Cuenod M, Do KQ. Redox Dysregulation in the
Pathophysiology of Schizophrenia and Bipolar Disorder: Insights from Animal Models. Antioxidants &
Redox Signaling, 18 (12), 1428-1443 (2013)
Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ. Early-Life Insults Impair Parvalbumin
Interneurons via Oxidative Stress: Reversal by N-Acetylcysteine. Biological Psychiatry, 73 (6), 574-582
(2013)
Cabungcal JH, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK, Do KQ. Perineuronal nets
protect fast-spiking interneurons against oxidative stress. Proceedings of the National Academy of
Sciences USA, 110 (22), 9130-9135 (2013)
Baumann PS, Crespi S, Marion-Veyron R, Solida A, Thonney J, Favrod J, Bonsack C, Do KQ, Conus P.
Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne): implementation of an early
intervention programme for psychosis in Switzerland. Early Interv Psychiatry, 7 (3), 322-328 (2013)
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. Schizophrenia Bulletin, 40 (5), 973-983 (2014)
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. Glutathione
deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.
Molecular Psychiatry, doi: 10.1038/mp.2014.88. [Epub ahead of print] (2014)
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*. Juvenile antioxidant treatment
prevents adult deficits in a developmental model of schizophrenia. Neuron, 83 (5), 1073-1084 (2014)
* Equal contribution
Duarte JM, Do K., Gruetter R. Longitudinal neurochemical modifications in the aging mouse brain
measured in vivo by (1)H magnetic resonance spectroscopy. Neurobiology of Aging, 35 (7), 16601668 (2014)
O'Donnell P, Do KQ, Arango C. Oxidative/Nitrosative stress in psychiatric disorders: are we there yet?
Schizophrenia Bulletin, 40 (5), 960-962 (2014)
Steullet P, Cabungcal JH, Cuenod M, Do KQ. Fast oscillatory activity in the anterior cingular cortex:
dopaminergic modulation and effect of perineuronal net loss. Front Cell Neurosci, doi:
10.3389/fncel.2014.00244. eCollection (2014)
REVIEW ARTICLES
Kim Q. Do. Gènes, environnement et neurodéveloppement: le cas de la schizophrénie. Revue
Médicale Suisse, 9: 1672-7 (2013)
Steullet P, Cabungcal JH, Monin A, Dwir D, O’Donnell P, Cuenod ., Do KQ. Redox dysregulation,
neuroinflammation, and NMDA receptor hypofunction: a “central hub” in schizophrenia
pathophysiology? Schizophrenia Research, doi: 10.1016/j.schres.2014.06.021 [Epub ahead of print]
(2014)
6
INVITED CONFERENCES & SYMPOSIA – PROF. KIM DO CUÉNOD –2013-2014
Prof. Kim Do Cuénod is regularly invited to share the results and perspectives of her research
program at major international events, research centres and universities.

Plenary Speaker, Neuroscience 2014 – 44th Annual Meeting of the Society for Neuroscience:
"Genes and Environment Interaction during Development: Redox Imbalance in
Schizophrenia", 17 November 2014, Washington DC, USA

Keynote speaker, Central Institute of Mental Health, Department of Psychiatry: "Oxidative
stress, NMDA hypofunction and neuroinflammation in schizophrenia: a translational
approach", 7 October 2014, Mannheim, Germany

Keynote speaker, Pfizer Inc., Neuroscience Research Unit, Psychiatry and Behavioral
Disorders: "Oxidative stress in psychosis: a translational approach towards new targets for
stage specific treatment", 13 May 2014, Cambridge, USA

Keynote speaker, Harvard Medical School, Department of Psychiatry: "Redox dysregulation in
schizophrenia: functional anomalies prevented by N-acetyl-cysteine in translational models",
12 May 2014, Boston, USA

Symposium (co-chair, speaker), Society of Biological Psychiatry, 69th Annual Scientific
Meeting: "Redox Dysregulation Affects Myelination And Parvalbumine Interneurons In
Schizophrenia Models", 10 May 2014, New York, USA

Symposium (speaker), Society of Biological Psychiatry, 69th Annual Scientific Meeting: "Redox
Dysregulation Models of Schizophrenia: Functional Anomalies Prevented By N-acetylcysteine", 8 May 2014, New York, USA

Satellite Symposium (organizer, speaker) "Schizophrenia: could it be prevented?", Society of
Biological Psychiatry, 69th Annual Scientific Meeting: "Oxidative stress in psychosis: a
translational approach", 7 May 2014, New York, USA

Keynote speaker, Kings College London, Institute of Psychiatry, Department of Psychosis
Studies: "Search for biomarkers and redox dysregulation in early psychosis: a translational
approach", 28 April 2014, London, UK

Inaugural Lesson, Lausanne University Hospital (CHUV): "Neurosciences et psychiatrie: le
développement du cerveau, toutes les chances et tous les risques", 8 April 2014, Lausanne,
Switzerland

Symposium (speaker), Swiss Society for Neuroscience, Annual Meeting: "Oxidative stress in
psychosis: a translational approach", 25 January 2014, Bern, Switzerland

Lecture, PhD course on "Advanced biomedical imaging methods and instrumentation",
Center for Biomedical Imaging (CIBM), Swiss Federal Institute of Technology (EPFL):
"Multimodal imaging in humans and animal models: towards early detection and novel drug
targets in psychosis", 13 December 2013, Lausanne, Switzerland

Workshop, Brocher Foundation, Neuroscience, Ethics and Law: New Challenges for Human
Identity, Freedom and Responsibility: "Neuroscience of the self in health and disease", 6
November 2013, Hermance, Switzerland

Symposium (speaker), 2nd SFCNS Congress, Swiss Federation of Clinical Neuro-Societies:
"Oxidative stress in psychosis: a translational approach", 6 June 2013, Montreux, Switzerland
7

Symposium (speaker), Society of Biological Psychiatry, 68th Annual Scientific Meeting: "The
Perineuronal Net Protects Fast-Spiking Parvalbumine Interneurons Against Oxidative Stress",
18 May 2013, San Francisco, USA

Conference, Le Relais – Association genevoise de soutien aux proches de personnes souffrant
de troubles psychiques: "Schizophrénie: la recherche progresse", 13 May 2013, Geneva,
Switzerland

Symposium (speaker), CINP Thematic Meeting, Pharmacogenomics and Personalised
Medicine in Psychiatry: "Redox imbalance in schizophrenia and its improvement by N-acetylcysteine", 21 April 2013, Jerusalem, Israel

Conference, Institute of Anatomy and Cell Biology, Università Cattolica del S. Cuore: "Redox
dysregulation in schizophrenia: a translational approach", 5 April 2013, Rome, Italy

Conference, l'îlot – Association vaudoise de proches de personnes souffrant de
schizophrénie: "Schizophrénie: la recherche progresse", 6 March 2013, Lausanne,
Switzerland
OBJECTIVES
On the clinical side, research has been conducted in a cohort of first episode psychosis (FEP) patients
in order to confirm the presence of neurobiological markers observed in chronic patients. In the
coming years, the aim is:
1) to consolidate results in a larger cohort of FEP patients, and
2) to extend the study to an “At-Risk Mental State” (ARMS/prodrome) cohort of subjects, in
order to explore whether previously identified multilevel markers in FEP are also present in
UHR (Ultra High Risk) patients and whether they represent stable markers or markers of
progression during the prodromal phase;
3) to identify new and more efficient molecules for the development of innovative treatments
and preventive measures.
The main research questions are the following:
a) Are phenomena that are well documented at the chronic stage also present at the beginning
of illness?
b) Are there stage specific phenomena that could be used as bio-markers and treatment
targets?
c) What are the underlying mechanisms driving the modifications of brain structure?
We thus aim to provide valid neurobiological markers for:
1) the early identification of patients;
2) the definition of the various stages of the disease;
3) the assessment of illness progression;
4) the development of new therapeutic tools.
8
CONCLUSION
The work carried out with a long-term vision by the team of the Unit for Research in Schizophrenia
(URS) is highly fruitful. The translational research program that has been developed step by step over
the last 15 years is presently recognized as a scientific approach unique in its kind. The interactions
between clinicians and researchers, as well as the confrontation of observations made in patients
and in experimental models, lead to essential developments in the exploration and knowledge of
schizophrenia, and more generally of psychosis. Such an approach represents a pioneer achievement
in the field of psychiatry.
The impact and visibility of the studies conducted by the research group directed by Prof. Kim Do
Cuénod was confirmed by the following events in 2014:

Given her exceptional scientific accomplishments, Prof. Kim Do Cuénod was elected
Individual Member of the Swiss Academy of Medical Sciences (SAMS) at the session held by
the SAMS Senate on 20 May 2014. This election represents a very high distinction and
emphasizes the excellence of Kim Do Cuénod's career in the field of biological psychiatry.

A video clip on the translational research program directed by Prof. Kim Do Cuénod and her
clinician colleague Prof. Philippe Conus was produced at the request of the American
Psychiatric Association (APA), and broadcasted during its Annual Meeting, which took place
at the beginning of May 2014, in New York. APA had chosen 5 research centres outside the
United States for such a presentation: 1 in Japan, 1 in Shanghai and 3 in Europe, among
which the Unit for Research in Schizophrenia (URS) in Lausanne. APA's choice represents a
great honor and a first-rate acknowledgment of the work carried out at the URS. The clip can
be accessed on the Website of the Alamaya Foundation, www.alamaya.net (page Videos).

Prof. Kim Do Cuénod was interviewed on the French Channel of the Swiss National Radio
(Radio Suisse Romande la 1ère) in the context of a scientific program called CQFD. The
edition of September 4th, 2014, focused on "News about schizophrenia"; the results of two
studies conducted by the URS were presented and commented by Kim Do Cuénod. The
interview can be accessed on the Website of the Alamaya Foundation (page Media).

Prof. Michel Cuénod, Chair of the Alamaya Foundation, invited professor at the University
of Lausanne and scientific adviser of the URS, was interviewed on the French Channel of
the Swiss National Radio (Radio Suisse Romande la 1ère) in the context of the CQFD
program broadcasted on March 17th, 2014. The program entitled "People with schizophrenia
have a life" was aired on the occasion of the 11th edition of the "Journées de la
Schizophrénie" (Days of Schizophrenia), a yearly event to raise awareness on schizophrenia
among the general public, which, in 2014, took place from 17 to 23 March. The interview can
be accessed on the Website of the Alamaya Foundation (page Media).
9
ANNEX I
CHUV
Centre Hospitalier Universitaire Vaudois
COMMUNIQUÉ DE PRESSE
GLUTATHIONE DEFICIT AFFECTS WHITE MATTER INTEGRITY IN PREFRONTAL CORTEX AND
IMPAIRS BRAIN CONNECTIVITY IN SCHIZOPHRENIA
Aline Monin, Philipp S. Baumann, Alessandra Griffa, Lijing Xin, Ralf Mekle, Margot Fournier,
Christophe Butticaz, Magali Klaey, Jan-Harry Cabungcal, Pascal Steullet, Carina Ferrari, Michel
Cuenod, Rolf Gruetter, Jean-Philippe Thiran, Patric Hagmann, Philippe Conus, Kim Q. Do.
Molecular Psychiatry, 2014
Chez les patients souffrant de schizophrénie on observe, entre autres, des anomalies des fibres qui
assurent les connexions entre différentes parties du cerveau. Le groupe de recherche de la Prof. Kim
Do Cuénod (Centre de neurosciences psychiatriques, Département de psychiatrie, CHUV-UNIL), en
collaboration avec le Prof. Philippe Conus (Service de psychiatrie général, Département de
psychiatrie CHUV-UNIL), le Prof. Patric Hagmann (Département de radiologie CHUV) et le Prof. Rolf
Gruetter (Centre d’imagerie biomédicale EPFL), vient de publier un article dans le prestigieux journal
Molecular Psychiatry dans lequel les mécanismes responsables de ces défauts de connectivité ont été
étudiés et leur cause en partie élucidée.
Ces résultats démontrent qu’une mauvaise régulation de l’équilibre entre oxydations et réductions
pendant le développement du cerveau pourrait jouer un rôle important dans le développement de la
schizophrénie. Les fibres nerveuses sont entourées d’une gaine isolante (la myéline) formée par des
cellules spéciales (les oligodendrocytes). Ces cellules sont particulièrement sensibles à un excès
d’oxydation. Une doctorante travaillant sous la supervision de la Prof. Kim Do Cuénod, Mme Aline
Monin, a montré que le déficit d'une molécule normalement abondante et protectrice contre les
oxydations (le glutathion) entraîne une insuffisance des cellules formatrices de myéline et de la
myélinisation du cortex. Elle a également montré que l'anomalie dans le développement de ces
cellules formatrices de myéline est liée à une dérégulation de l’activité d’un enzyme appelée "Fyn
kinase".
L’intérêt majeur de cette recherche est le fait que les résultats obtenus dans des modèles
expérimentaux ont également été identifiés chez les patients: la Fyn kinase est également dérégulée
dans les cellules de peau provenant de patients porteurs d’une anomalie génétique entravant la
formation du glutathion et exposées à un stress oxydatif. D’autre part, plus le taux de glutathion
(mesuré par résonance magnétique spectroscopique) dans le cortex préfrontal médian est élevé,
meilleure est l’intégrité des fibres nerveuses d’un faisceau appelé "cingulum" (mesurée par Diffusion
Spectrum Imaging), comme l’ont montré les Drs Philipp Baumann, Alessandra Griffa et Lijing Xin. Ces
résultats confirment le rôle déterminant de l’équilibre entre oxydations et réductions lors du
développement des fibres nerveuses, et son implication probable dans l’origine des défauts de
connectivité chez les patients souffrant de schizophrénie. Ils ouvrent la voie à l’établissement de
biomarqueurs et de nouveaux mécanismes d’intervention précoce.
10
ANNEX II
CHUV
Centre Hospitalier Universitaire Vaudois
COMMUNIQUÉ DE PRESSE
JUVENILE ANTIOXIDANT TREATMENT PREVENTS ADULT DEFICITS IN A
DEVELOPMENTAL MODEL OF SCHIZOPHRENIA
Jan-Harry Cabungcal, Danielle S. Counotte, Eastman M. Lewis, Hugo A. Tejeda, Patrick Piantadosi,
Cameron Pollock, Gwendolyn G. Calhoon, Elyse M. Sullivan, Echo Presgraves, Jonathan Kil, L. Elliot
Hong, Michel Cuenod, Kim Q. Do, Patricio O’Donnell
Neuron, 2014
Le laboratoire de la Prof. Kim Do Cuénod (Centre de neurosciences psychiatriques, Département de
psychiatrie, CHUV-UNIL) avait montré dans un modèle animal de la schizophrénie qu’une insuffisance
de la lutte contre les oxydations entraîne des anomalies de certains neurones essentiels pour les
activités cognitives (appelés "parvalbumine interneurones" ou PVI). Ces anomalies ont également été
observées dans le cerveau des patients. Cela suggérait que ce contrôle déficient pourrait être une
des causes de la schizophrénie. Comme l’intervention portait au niveau génétique sur le système de
contrôle des oxydations lui-même, il était intéressant d’observer qu’un stress oxydatif affectait
sélectivement ces neurones PVI.
Une nouvelle étape dans la recherche a maintenant été franchie, grâce à une collaboration avec
l’équipe du Prof. Patricio O’Donnell de l’Université du Maryland à Baltimore (USA). L’article publié
dans la revue Neuron le 3 septembre 2014 porte sur un autre modèle bien établi de la schizophrénie
qui consiste à faire une petite lésion d’une structure du cerveau, l’hippocampe ventral, chez le rat
nouveau-né. Ces animaux présentent eux aussi, à l’âge adulte, des manifestations pathologiques
typiques de la maladie.
L’équipe de Lausanne a observé que ces animaux présentent également un stress oxydatif et des
anomalies des neurones PVI, bien que leur système de régulation des oxydations n’ait pas été
impliqué, prouvant ainsi que le stress oxydatif peut avoir des origines variées. Le plus fascinant, c’est
qu’un traitement avec un antioxydant, la N-acétyle-cystéine, permet non seulement de protéger
l’animal contre l’oxydation des PVI, mais corrige aussi les autres anomalies physiologiques et
comportementales connues de ce modèle. Il semble donc que, pendant le développement du
cerveau, des causes multiples sont susceptibles d’induire un stress oxydatif neuronal sélectif
conduisant au développement de la maladie. Cette découverte ouvre la voie à de nouveaux
traitements.
11
ANNEX III
Model of Schizophrenia Cortical Deficits Reversed With Antioxidants
August 6, 2014. In a new study published online August 6 in Neuron, an international collaboration
offers up evidence linking the reported alterations in cortical interneurons in schizophrenia to
oxidative stress.
Kim Do and colleagues at Lausanne University Hospital in Switzerland teamed up with Patricio
O'Donnell's group at the University of Maryland in Baltimore to test the Lausanne group's longstanding hypothesis of oxidative stress in schizophrenia by using the neonatal ventral hippocampal
lesion (NVHL) model that O'Donnell has employed to probe subtle miswiring of the prefrontal cortex.
The authors report evidence that NVHL produces oxidative stress in rat cortical interneurons,
particularly those expressing parvalbumin, and that giving the animals an antioxidant throughout
most of postnatal development, or even just in the last stages before adulthood, can reverse this
finding, along with various deficits in neuronal chemistry and electrophysiology and brain function.
Linking up hypotheses
For many years, the two research groups have been working on separate hypotheses: O'Donnell's lab
has investigated the delayed effects of neonatal hippocampal lesions in rats on the development of
wiring in the prefrontal cortex. The researchers have proposed that the abnormalities that arise only
in rat "adolescence" can model some aspects, particularly in the dopaminergic system, of
schizophrenia pathophysiology (see SRF related news report and SRF related conference report). For
their part, Do and Michel Cuenod have pursued evidence that the nervous system of people with
schizophrenia is awash in reactive oxygen species that can harm neurons in various ways. In
particular, they have focused on the possibility of a shortage of glutathione, which scavenges these
oxidative molecules (reviewed in SRF related conference report).
In their joint study, co-first authors Jan-Harry Cabungcal, Danielle Counotte, Eastman Lewis, and their
colleagues lesioned the ventral hippocampus in rat pups (postnatal days 7-9) and exposed them to
the antioxidant N-acetyl cysteine (NAC) from P5 until P60, first through their mothers and later
directly via drinking water.
Consistent with previous reports, the lesions resulted in changes to interneurons in prefrontal cortex
(PFC), specifically to the expression of parvalbumin (PV) in NVHL rats versus sham-operated animals.
NAC treatment reversed these changes, and in support of the idea that oxidative stress was a factor
in the reduction in PV, the authors found significantly higher levels of the DNA oxidation marker 8oxo-dG in cortical pyramidal cells and interneurons of the NVHL rats at P21.
The immunohistochemistry data were supported by electrophysiology in cortical slice and in-vivo
preparations. Well-known abnormalities in PFC pyramidal cell synaptic function of NVHL mice were
also corrected by the NAC treatment.
Finally, Cabungcal and colleagues zoomed out to look at information processing and sensorimotor
gating, using mismatch negativity and prepulse inhibition (PPI) tests to probe for deficits that have
12
been found in people with schizophrenia. In both cases, NAC treatment normalized the alterations
stemming from the neonatal lesions.
The authors also addressed one possible critique that the beneficial effects were due to effects on
glutamate neurotransmission via the cysteine-glutamate transporter. However, both ebselen and
apocynin antioxidants that do not affect glutamate levels rescued the PPI deficits in NVHL animals.
Questions for the future
"Our data suggest that oxidative stress in PFC is a core feature mediating alterations induced by the
NVHL, and antioxidant treatment prevents these alterations," conclude the researchers.
How would the NVHL have produced oxidative stress? The authors speculate that the reduction in
glutamatergic input during development places the PV-expressing interneurons in PFC under
oxidative stress, citing evidence that NMDA receptor blockade can have this effect (see SRF related
news report). However, they also note that this model of prefrontal dysfunction does not have to
accurately reflect processes of schizophrenia in order to reproduce the pathophysiology of the
disease.
The results are certainly intriguing, given that they present a possible therapeutic option that could
be applied early in the disease, or even in the prodrome Cabungcal and colleagues were able to
significantly improve prepulse inhibition by giving NAP beginning in rat adolescence (P35). The
compound appears to have few major side effects, and it is currently used as a non-regulated
supplement, though it would be hard to predict its effects on the developing nervous system. Hakon
Heimer.
Reference:
Cabungcal JH, Counotte DS, Lewis EM, Tejeda HA, Piantadosi P, Pollock C, Calhoon GG, Sullivan EM,
Presgraves E, Kil J, Hong LE, Cuenod M, Do KQ, O'Donnell P. Juvenile Antioxidant Treatment Prevents
Adult Deficits in a Developmental Model of Schizophrenia. Neuron. 2014 Aug 12. Abstract
13
ANNEX IV
Science News
... from universities, journals, and other research organizations
Neuron Loss in Schizophrenia and Depression Could Be Prevented, Study
Suggests
Mar. 13, 2013 — Gamma-aminobutyric acid (GABA) deficits have been implicated in schizophrenia
and depression. In schizophrenia, deficits have been particularly well-described for a subtype of
GABA neuron, the parvalbumin fast-spiking interneurons. The activity of these neurons is critical
for proper cognitive and emotional functioning.
It now appears that parvalbumin neurons are particularly vulnerable to oxidative stress, a factor that
may emerge commonly in development, particularly in the context of psychiatric disorders like
schizophrenia or bipolar disorder, where compromised mitochondrial function plays a role.
Parvalbumin neurons may be protected from this effect by N-acetylcysteine, also known as
Mucomyst, a medication commonly prescribed to protect the liver against the toxic effects of
acetaminophen (Tylenol) overdose, reports a new study in the current issue of Biological Psychiatry.
Dr. Kim Do and collaborators, from the Center for Psychiatric Neurosciences of Lausanne University
in Switzerland, have worked many years on the hypothesis that one of the causes of schizophrenia is
related to vulnerability genes/factors leading to oxidative stress. These oxidative stresses can be due
to infections, inflammations, traumas or psychosocial stress occurring during typical brain
development, meaning that at-risk subjects are particularly exposed during childhood and
adolescence, but not once they reach adulthood.
Their study was performed with mice deficient in glutathione, a molecule essential for cellular
protection against oxidations, leaving their neurons more exposed to the deleterious effects of
oxidative stress. Under those conditions, they found that the parvalbumin neurons were impaired in
the brains of mice that were stressed when they were young. These impairments persisted through
their life. Interestingly, the same stresses applied to adults had no effect on their parvalbumin
neurons.
Most strikingly, mice treated with the antioxidant N-acetylcysteine, from before birth and onwards,
were fully protected against these negative consequences on parvalbumin neurons.
"These data highlight the need to develop novel therapeutic approaches based on antioxidant
compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects,"
said Do. "To give an antioxidant from childhood on to carriers of a genetic vulnerability for
schizophrenia could reduce the risk of emergence of the disease."
"This study raises the possibility that GABA neuronal deficits in psychiatric disorder may be
preventable using a drug, N-acetylcysteine, which is quite safe to administer to humans," added Dr.
John Krystal, Editor of Biological Psychiatry.
14
ANNEX V
ACTUALITES NCCR-SYNAPSY
Prévenir la schizophrénie chez les enfants
15.03.13 - En intervenant tôt sur le développement du cerveau, avec un traitement
approprié, il serait possible de diminuer l’apparition de troubles schizophréniques, relève
une étude du groupe de recherche du Prof. Kim Do, publié aujourd'hui dans la version
imprimée de "Biological Psychiatry".
L'Unité de recherche sur la schizophrénie du CHUV, dirigée par le Prof. Kim Do, membre du NCCR
Synapsy, travaille depuis plusieurs années sur l’hypothèse qu’une des causes de la schizophrénie est
liée à des gènes de risque associés à des stress oxydatifs causés entre autres par des infections,
inflammations, traumatismes et stress psychique, durant le développement du cerveau. L'étude d'un
modèle animal (souris), dont la synthèse du glutathion est diminuée entraînant ainsi un risque élevé
de stress oxydatifs, permet d’explorer les origines et l'évolution de certaines anomalies observées
dans le cerveau des patients.
Une destruction irréversible
L'article publié en ligne en novembre 2012 et aujourd'hui imprimé dans la revue Biological Psychiatry
porte sur une étude impliquant le modèle animal pauvre en glutathion. Cette substance produite par
l'organisme est un important régulateur des oxydations et un agent protecteur essentiel pour les
cellules nerveuses. Les chercheurs ont étudié une classe particulière de neurones inhibiteurs - dits "à
parvalbumine” - qui jouent un rôle capital dans toutes les activités du cortex, qu’il s’agisse de
mémoire, d’attention ou d’émotion. Ces neurones sont moins nombreux dans le cortex frontal des
patients souffrant de schizophrénie et du modèle animal. L'étude démontre que ces derniers sont
particulièrement sensibles aux excès d’oxydants (stress oxydatif) pendant l’enfance et la jeunesse et
que cette vulnérabilité disparaît à l’âge adulte. De plus, la destruction de ces neurones est durable et
irréversible, d’où l’importance de l’intervention précoce.
Un antioxydant pour traitement
Fait remarquable, en administrant à l'animal un antioxydant appelé N-acétyl-cystéine dès avant sa
naissance, on le protège totalement contre les déficits des neurones “à parvalbumine”. Il apparaît
donc qu’un traitement préventif approprié est susceptible d’éviter les conséquences défavorables
qui résultent de la combinaison d’une anomalie génétique (déficit en glutathion ou autres gènes de
risque) avec un stress oxydatif pendant le développement du cerveau. Ces résultats revêtent une
importance particulière du fait que de nombreux événements adverses au cours de l’enfance et de la
jeunesse, couplés à la vulnérabilité génétique peuvent provoquer un stress oxydatif. Sans l’apport
d’un traitement préventif approprié, ces traumatismes pourraient avoir un effet délétère à long
terme, s’ils surviennent pendant l’enfance et la période péripubertale.
15
ANNEX VI
LAUSANNE
15 mars 2013 15:34; Act: 15.03.2013 15:59
Des antioxydants pour prévenir la schizophrénie
D'après une étude menée par des chercheurs lausannois sur des souris, des antioxydants
pourraient être administrés à titre préventif aux jeunes touchés par un risque de
schizophrénie.
L'équipe de Kim Do, responsable de l'Unité de recherche sur la schizophrénie du CHUV et
professeure associée à l'Université de Lausanne, a administré à des souriceaux un médicament
antioxydant bien connu, la N-acétylcystéine, utilisée notamment contre la bronchite et bien
supportée par l'être humain.
Les dommages causés à certains neurones par un stress oxydatif pourraient en effet être en cause
dans la genèse de la schizophrénie. C'est en particulier le cas des interneurones exprimant la
parvalbumine (PV), une protéine impliquée dans la régulation cellulaire et la production de
substances de signalisation.
On parle de stress oxydatif lorsque la cellule est agressée par un excès de certaines molécules
d'oxygène et que son système de détoxification est dépassé. Cela peut être le cas lors d'infections et
inflammations mais aussi lors d'évènements négatifs vécus durant l'enfance et la jeunesse.
Les chercheurs lausannois ont constaté que les interneurones PV sont particulièrement sensibles au
stress oxydatif, comme ils l'écrivent dans la revue «Biological Psychiatry».
Effet protecteur
Pour leur étude, ils ont utilisé des souriceaux privés d'un gène déterminant pour une molécule
protégeant de l'oxydation et les ont soumis à des situations effrayantes. Résultat: une perturbation
accrue des interneurones PV.
Chez des souris adultes par contre, le stress n'avait pas d'effet dommageable. Idem chez des
souriceaux auxquels les scientifiques avaient administré de l'antioxydant N-acétylcystéine avant et
après la naissance. Leurs interneurones PV étaient entièrement protégés.
Selon les chercheurs, l'administration de N-acétylcystéine à de jeunes personnes à risque pourrait
prévenir la schizophrénie. «Ces données soulignent la nécessité de développer des médicaments sur
la base d'antioxydants qui pourraient être remis à des enfants et adolescents à risque», estime le Dr
Do dans un communiqué de l'éditeur Elsevier.
(afp)
16