A virtual brain helps decrypt epilepsy

cerveau virtuel

The Virtual Brain: reconstruction of brain regions and where they are connected. The green cubes indicate the center of brain regions that are connected


Researchers at CNRS, INSERM, Aix-Marseille University and AP-HM have just created a virtual brain that can reconstitute the brain of a person affected by epilepsy for the first time. From this work we understand better how the disease works and can also better prepare for surgery. These results are published in Neuroimage, on July 28, 2016.


Worldwide, one percent of the population suffers from epilepsy. The disease affects individuals differently, so personalized diagnosis and treatment are important. Currently we have few ways to understand the pathology’s mechanisms of action, and mainly use visual interpretation of an MRI and electroencephalogram. This is especially difficult because 50% of patients do not present anomalies visible in MRI, so the cause of their epilepsy is unknown.

Researchers have succeeded for the first time in developing a personalized virtual brain, by designing a base “template” and adding individual patient information, such as the specific way the brain’s regions are organized and connected in each individual. Mathematical models that cause cerebral activity can be tested on the virtual brain. In this way, scientists have been able to reproduce the place where epilepsy seizures initiate and how they propagate. This brain therefore has real value in predicting how seizures occur in each patient, which could lead to much more precise diagnosis.


Moreover, 30% of epileptic patients do not respond to drugs, so their only hope remains surgery. This is effective if the surgeon has good indications of where to operate.

The virtual brain gives surgeons a virtual “platform.” In this way they can determine where to operate while avoiding invasive procedures, and especially prepare for the operation by testing different surgical possibilities, seeing which would be most effective and what the consequences would be, something that is obviously impossible to do on the patient.

In the long run, the team’s goal is to provide personalized medicine for the brain, by offering virtual, tailored, therapeutic solutions that are specific for each patient. The researchers are currently working on clinical trials to demonstrate the predictive value of their discovery. This technology is also being tested on other pathologies that affect the brain, such as strokes, Alzheimer’s, degenerative neurological diseases, and multiple sclerosis.


This work involves researchers at the Institut de Neurosciences des Systèmes (INSERM/AMU), the Centre de Résonance Magnétique Biologique et Médicale (CNRS/AMU/AP-HM), the Département Epileptologie et du Département Neurophysiologie Clinique at AP-HM, and the Epilepsy Center of Cleveland. It was done in the Fédération Hospitalo-Universitaire Epinext (


The Virtual Epileptic Patient: brain regions and their connections are rebuilt by computer. Digital simulations generate an electric signal similar to that generated by the brain during seizures. These simulations allow digital testing of new therapeutic strategies


Inserm, France’s rising research star according to Nature


(c) Macmillan Publishers Ltd

The French National Institute of Health and Medical Research (Inserm) is the only research institution in France listed in the World Top 100 institutions with the most progress in the last 3 years. This is indicated by the Nature Index 2016 Rising Stars, which highlights the big contribution of Inserm researchers to publications in the best 68 journals selected by Nature. This ranking identifies the most brilliant institutions to watch in 2016 and in the coming years.


Of 8,000 institutions reviewed, Inserm appears in 75th place among the institutions with the strongest progress. In three years, of a selection of 68 scientific journals rated best by Nature, the number of publications increased by 17.43%. Contributions from Inserm researchers published in the journal Science and the Nature Group Journals almost doubled in three years. Inserm is the only research institution in France listed in the Nature Index 2016 Rising Stars. Its presence in this index is all the more exceptional given that the index is naturally dominated by countries, such as China, that have very recently entered into international competition, and have exceptional growth in their number of publications.


For Professor Yves Lévy, Chairman and Chief Executive Officer of Inserm: “This indicator reflects our research policy, which encourages Inserm researchers to publish in the best journals because they are talented. This index didn’t take into account medical journals specialising in clinical research, such as NEJM, JAMA or The Lancet, in which growth is 37%. Theses results confirm the place of Inserm in basic science and in clinical research.”


About Inserm

Founded in 1964, the French National Institute of Health and Medical research (Inserm) is a public science and technology institute, jointly supervised by the French Ministry of National Education, Higher Education and Research and the Ministry of Social Affairs, Health and women’s Rights. Inserm is the only French public research institute to focus entirely on human health with nearly 15000 researchers, engineers, technicians, post-doctoral students and more than 300 laboratories. The mission of its scientists is to study all diseases, from the most common to the rarest. Inserm is a member of Aviesan, the French National Alliance for Life Sciences and Health founded in 2009. Other founding members of Aviesan : CEA, CNRS, CHRU, CPU, INRA, INRIA, Institut Pasteur, IRD.

Omega-3 fatty acids and stress management: growing links

nutrition poisson légumes aliments


The relationship between omega-3 fatty acid intake and adaptation to stress or anxiety is becoming clearer. Back in 2011, a team of researchers from INRA and Inserm showed that reducing the intake of omega-3 fatty acids in mice increased their stress. This phenomenon may be linked to impairment of the brain’s ability to produce endogenous cannabinoids, the “endocannabinoids,” brain lipids that control synaptic memory. To better understand the endocannabinoid-dependent links between anxiety and synaptic plasticity, the research team continued its experiments by testing different models of behavioural stress on the rodents. These studies are the subject of an article published in the journal Cell Reports on 21 July.

Mice do not respond equally to stress. An observation made by an INRA/Inserm research team who, after submitting the rodents to a battery of tests related to behaviour stress – isolation, maze or anxiogenic environment – found that some subjects were naturally resilient, or in other words, more resistant to stress. This ability may be related to better plasticity in the neurons of the accumbens nucleus, an area of the brain associated with regulation of the emotions and of stress, where endocannabinoids play a key role in memory at synapse level.

To confirm this relationship, mice showing several anxiety-related symptoms received a treatment to stimulate endocannabinoid production in the accumbens nucleus. Result: the scientists observed an attenuation of anxiety in these mice. For the first time, it has been proven that there is a relationship between anxiety and the levels of endocannabinoids produced by the brain. These results further emphasise the therapeutic potential of molecules that modulate the natural production of endocannabinoids, including dietary omega-3 fatty acids.

A milestone has thus been reached in demonstrating the protective effect of omega-3 fatty acids on the impairment of the brain’s ability to produce endocannabinoids. Ultimately, the idea is to understand how omega-3 fatty acids exert a protective action in response to the impairment of endocannabinoid-dependent plasticity in the accumbens nucleus, a part of the brain that constitutes the neurobiological substrate for anxiety.

This opens new perspectives in understanding the role of omega-3 fatty acids in the management of stress by the brain. The next studies will be aimed at better understanding the role of dietary omega-3 fatty acids in protecting the plasticity of the accumbens nucleus, and hence their ability to stimulate endocannabinoid production in a situation of stress.

Long term correction of hyperbilirubinemia in animal models of Crigler-Najjar syndrome after AAV vector-mediated liver gene transfer

Dr. Federico MINGOZZI, Team Leader of the Immunology and Liver Gene Transfer unit at Généthon, (Inserm U951/UPMC), France, has demonstrated the long-term efficacy of an optimized AAV-UGT1A1 vector for the correction of Crigler-Najjar syndrome (CN) in two different animal models of the disease. This work, published in July 20, 2016 in Molecular Therapy Methods and Clinical Development was supported by the AFM-Telethon.


Crigler-Najjar syndrome (CN) is a rare inherited liver disorder characterized by a deficiency of the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1). This enzyme converts bilirubin, a yellow pigment, into conjugated bilirubin. After conjugation, bilirubin becomes water soluble and is excreted in the bile and further eliminated from the organism. UGT1A1 enzyme deficiency leads to the accumulation of bilirubin in all body tissues, especially in the brain. If not treated, the brain accumulation of bilirubin leads to neurological damage and death.

Currently, treatment of CN is based on the ability of blue light to degrade bilirubin. Based on that, patients are exposed to phototherapy for 10 to 12 hours per day. Although the treatment is relatively efficacious and keeps bilirubin under the toxicity level it presents several disadvantages. In fact the long phototherapy sessions prevent patients from conducting a normal life, resulting in lack of compliance and other issues. Additionally, the time of exposure to phototherapy increases with the age due to the decreased body surface/mass ratio, and the therapy does not prevent potentially lethal bilirubin spikes associated for example with trauma or infections. The only curative treatment for CN is liver transplantation, which also presents significant potential risks and long-term complications.
Hence, gene therapy represents an alternative curative option to correct the genetic defect, restore the enzyme expression and the consequent bilirubin conjugation. Researchers at Genethon have designed an optimized AAV vector expressing the UGT1A1 transgene and tested it in two animal models of Crigler-Najjar syndrome, the Gunn rat and in UGT1A1 deficient mouse.

Following a single administration of the therapeutic vector, the researchers observed safe and efficient correction of the disease, with disappearance of bilirubin from serum consequent to restoration of the UGT1A1 activity in liver. Animals were followed for more than one year after vector injection, demonstrating long-lasting efficacy of the approach.
This work is the result of the coordinated efforts of a European Network of collaborators that includes the laboratory of Dr. Mingozzi at Genethon, the laboratories of Dr. Bosma at the Academic Medical Center in the Netherlands and Dr. Muro at the International Centre for Genetic Engineering and Biotechnology in Italy, the Crigler-Najjar patients associations of France, Italy and the Netherlands, and several clinical centers in Europe.
Based on these results, Genethon researchers are now preparing a phase I/II clinical trial that will open for enrollment in the near future.

An antibody-based drug for multiple sclerosis

Inserm Unit U919, directed by Prof. Denis Vivien (“Serine Proteases and Physiopathology of the Neurovascular Unit”) has developed an antibody with potential therapeutic effects against multiple sclerosis. The study, directed by Fabian Docagne and published in Brain, paves the way for a new strategy to control the disease.

Multiple sclerosis is a disease that affects the central nervous system, particularly the brain and spinal cord. It is the most common cause of neurological disability in young adults.

The disease is considered autoimmune since the immune system, which is there to protect the body from external assault, attacks its own constituents. The cells of the immune system, particularly the lymphocytes, bring about the destruction of the myelin sheath that surrounds and protects the extensions (axons) of the neurons. This demyelination, which marks the beginning of axon degeneration, disrupts the transmission of nerve impulses. Lesions in the form of “plaques” are dispersed over the brain and spinal cord. They cause symptoms that vary greatly from one individual to another.

Usually, the disease is characterised by exacerbations, with the appearance of motor, sensory and cognitive disorders, followed by remission a few weeks later. But with the passage of years, these symptoms can progress to irreversible disability. Current treatments reduce the exacerbations and improve the quality of life of patients, but do not control the progression of the disease.

sclérose en plaq

(C) Inserm/Fumat, Carole

In order for the cells of the immune system circulating in the bloodstream to reach the central nervous system, they must penetrate the blood-brain barrier (haematoencephalic barrier) and blood-spinal cord barrier (haematomedullary barrier).

During previous work on a mouse model of stroke, the team from Inserm Unit 919 studied a factor involved in opening the blood-brain barrier, the NMDA receptor. In particular, they observed that blocking the interaction of this receptor with tPA (a member of the serine protease family) has beneficial effects associated with maintaining the integrity of the barrier.

In this study, the researchers developed a strategy for blocking the interaction of tPA with the receptor, in multiple sclerosis. In the laboratory, they developed a monoclonal antibody (Glunomab®) directed against the specific site on the NMDA receptor to which tPA binds.

schéma docagne english

(C) Fabian Docagne, Inserm/Servier Medical Art

In cellular models of the human blood-brain and blood-spinal cord barriers, the use of this antibody prevented opening of the barrier under inflammatory conditions, limiting the entry of lymphocytes. The team then tested the therapeutic effects of the antibody in an experimental mouse model of multiple sclerosis. After intravenous injection of Glunomab, the progression of motor disorders (partial or total paralysis of the limbs), as assessed by a clinical score, was blocked. In these treated mice, this effect was associated with reduced infiltration of lymphocytes into the nervous tissue, and reduced demyelination.

By thus preventing myelin destruction by the cells of the immune system, this strategy might represent a promising therapy for the control of multiple sclerosis.

A patent application has been filed on this work.

Attacks and risks of post-traumatic stress

In a traumatic event, such as the attacks on Paris on 13 November 2015, and on Nice on 14 July 2016, the risk for victims and witnesses of developing post-traumatic stress disorder (PTSD) is high.

PTSD is characterised by several symptoms: the person relives the event in the form of recurrent memories, nightmares or flashbacks, avoids anything that reminds him/her of the moment, is in a constant state of alert, and shows difficulty in concentrating. Changes in mood may also occur.

At Inserm, there is ongoing active research to better identify the people most at risk of developing post-traumatic stress disorder, and thereby improve their care.

In the Phoenix study, which evaluates the impact of a trauma or chronic stress on the physical and mental health of 123 patients for a one-year period, work carried out by Isabelle Chaudieu, Inserm Unit 1061 “Neuropsychiatry: Epidemiological and Clinical Research,” is aimed at identifying biomarkers to predict PTSD. Her team is trying to determine whether the allostatic load might make it possible to predict the development of PTSD.

By collecting and analysing personal accounts from 1,000 volunteers over a ten-year period, the 13 Novembre programme (CNRS – Inserm), codirected by historian Denis Peschanski and neuropsychologist Francis Eustache, is aimed at studying the construction and evolution of memory after the attacks of 13 November 2015, and the interaction between individual and collective memory. The researchers will try to better understand the impact of traumatic shocks on the memory, and identify brain markers associated with resilience to trauma.

Read the press release “Attacks: 13-Novembre, a novel research program on traumatic memories.”

fire rescue

New findings from analysis of malignant tumour progression

Researchers from Paris Descartes University, CNRS, Inserm, University Paris-Est Créteil (UPEC) and the Paris Public Hospitals (AP-HP) have shown that analysis of epigenetic modifications could be used as a universal marker for monitoring tumour DNA circulating in the bloodstream of patients with colorectal cancer. This study is based on hypermethylation analysis of two genes (WIF1 and NPY) using a cutting-edge method: droplet-based digital PCR[1]. These results were published on 1 June 2016 in the journal Clinical Chemistry.

U768, Développement normal et pathologique du système immunitaire

Blood samples

(c) Inserm/Latron, Patrice

Procedures for diagnosing and monitoring the various forms of cancer have evolved greatly in recent years. Thus, the liquid biopsy, which consists of analysing genetic markers for cancer present in the patient’s bloodstream, rather than the tumour, is becoming common. This method has the advantage of being noninvasive, and of offering precise mapping of the state of progress of a patient’s tumours by analysing the DNA released from them and disseminated in the bloodstream.


Moreover, it has been recently proved that mutations in tumour DNA might be responsible for resistance to some therapies. “Our research is mainly focused on colorectal cancer. One of our strategies involves analysing tumour-specific genetic markers by sequencing, and then looking for the presence or absence of one or more of these marker(s) using blood samples. Thanks to this, we can precisely measure the efficacy of a therapy or the recurrence of a cancer,” explains Valérie Taly, CNRS Research Director.

This research has thus shown that there is a wide variety of genetic markers in tumours, making analysis difficult if not impossible. “We had calculated, for example, that some thirty different tests would be needed to monitor slightly more than half of the patients in our cohort. Since the other half of the patients had rare or even unique mutations, it would have been necessary to develop nearly one test per patient,” continues Valérie Taly.

It was therefore necessary to find markers that may be universal, and which would enable monitoring of a maximum of patients with a minimum of tests. In addition, by collaborating with the team led by Professor Iradj Sobhani, from Henri Mondor Hospital, AP-HP, who demonstrated epigenetic markers for tumour DNA, the group led by Dr Valérie Taly and Professor Pierre Laurent Puig, from Georges Pompidou European Hospital, AP-HP, proceeded to analyse blood from cancer patients using droplet-based digital PCR. This method consists of dividing a biological sample into millions of microscopic compartments (in this case droplets a few picolitres in size), such that each compartment contains no more than one target DNA molecule. Each target DNA molecule can then be tested individually, enabling the achievement of a sensitivity and precision unattainable by conventional methods. This procedure showed that hypermethylation of the WIF1 and/or NPY genes was detectable in 100% of the tumours, whether these were localised or metastatic, and that these markers could also be detected in the patients’ blood.


“Furthermore, we showed that the detection of circulating tumour DNA and its dynamics by monitoring a particular mutation completely correlated with its detection by monitoring these hypermethylations. This allowed us to conclude that characterisation of these methylation markers could enable monitoring of all patients from the cohort we mentioned earlier,” says Valérie Taly. With these results, the scientists have shown that it is possible to both monitor the efficacy of a treatment in patients with advanced cancer, and detect possible recurrences earlier than the methods in current use.

This study involves researchers from the “Personalized Medicine, Pharmacogenomics, Therapeutic Optimization” laboratory (UMR-S1147, Paris Descartes University/Inserm, CNRS SNC 5014), the EA7375 team from University Paris-Est Créteil (UPEC) and physicians from Henri-Mondor Hospital, AP-HP, Georges Pompidou University Hospital, AP-HP, Reims University Hospital, Ambroise Paré Hospital, AP-HP, Clermont-Ferrand University Hospital, Val d’Aurelle Paul Lamarque Centre and RainDance Technologies.

[1] polymerase chain reaction or polymerase chain amplification.

Malaria: a genetically attenuated parasite induces an effective, long-lasting immune response

With nearly 3.2 billion people currently at risk of contracting malaria, scientists from the Institut Pasteur, the CNRS and Inserm have experimentally developed a live, genetically attenuated vaccine for Plasmodium, the parasite responsible for the disease. By identifying and deleting one of the parasite’s genes, the scientists enabled it to induce an effective, long-lasting immune response in a mouse model. These findings were published in the Journal of Experimental Medicine on July 18, 2016.

Anopheles stephensi infectée par Plasmodium berghei

Anopheles stephensi infectée par Plasmodium berghei. © Institut Pasteur

Despite increased prevention and eradication efforts over the past fifteen years, especially targeting mosquito vectors, malaria remains the parasitic disease that poses the biggest threat for the world’s population. Approximately 214 million cases and 438,000 deaths from malaria were recorded in 2015[1], mostly children under the age of five and pregnant women. An effective vaccine is needed to combat this disease, but the complex biological make-up of Plasmodium and the many strategies the parasite has evolved to outmaneuver the host immune response mean that developing a malaria vaccine is a difficult task. One notable feature of patients infected by the malaria parasite is the difficulty in mounting a long-lasting protective immune response. Premunition, or relative immunity, is only acquired after several years of exposure. An important feature during malaria infection is that the parasite prevents the establishment of immunological memory.

The team led by Salaheddine Mécheri in the Biology of Host-Parasite Interactions Unit (a CNRS / Inserm unit at the Institut Pasteur), working in cooperation with Robert Ménard from the Institut Pasteur’s Malaria Infection & Immunity Unit, decided to take an original approach to attenuate parasite virulence for effective vaccine development. The scientists genetically modified strains of the Plasmodium parasite by deleting the gene that codes for the HRF (histamine-releasing factor) protein.

The resulting mutants, which no longer expressed HRF, proved to be highly effective in triggering a potent immune response. The absence of HRF boosted the production of the IL-6 cytokine, known for its ability to stimulate the immune response, in the liver and the spleen. This conferred mice with protection from any potential reintroduction of the Plasmodium parasite, including highly virulent strains. This protection was long lasting as it was maintained for more than a year, suggesting that a long-term immunological memory had been established. The protection was also effective against all stages of the parasite’s life cycle. Finally, unlike the standard wild-type Plasmodium berghei strain, which does not induce a cellular or humoral response, this vaccine strain not only induced a cellular response (CD4 and CD8 T cells) but also triggered high levels of specific antibodies that recognized parasite antigens known to be vaccine targets.

The HRF mutants obtained in this study are the first genetically modified parasites whose mutation has a direct impact on the host’s immune response. Use of this target gene, or a similar strategy to stimulate immunity, could lead to the development of effective, long-lasting live vaccines for malaria.

“In recent years, the vaccine strategy of choice using live, genetically attenuated parasites to combat malaria has received renewed interest. The HRF mutant is a promising prototype in this respect, offering a rapid, long-lasting and wide-ranging protective effect,” commented Salaheddine Mécheri.

[1] WHO figures.

Objectives and performance contract signed between the State and Inserm for 2016–2020

On 11 July 2016, Mr Thierry Mandon, Secretary of State for Higher Education and Research, and the Chairman and CEO of the Institute, Professor Yves Lévy, signed the objectives and performance contract binding Inserm and the French State for the 2016–2020 period. The result of intense exchanges between Inserm and the relevant ministries, the contract defines the broad directions and actions that will be taken by the Institute in order to provide an environment conducive to the expression of talent, encourage the production of knowledge and best support its exploitation for societal, clinical or economic purposes, and enable laboratories to best respond to the new challenges and issues in the life sciences and health.

signature du contrat d'objectif INSERM

(c) Inserm – Mehrak Hans Lucas

Inserm has set itself 6 broad objectives for the next 5 years. These comprise 35 actions associated with specific performance indicators and time frames.


Objective 1: Support integrated and pluridisciplinary research, and produce knowledge of the highest standard

Inserm’s good results at international level are the result of the laboratories’ activity, based on unrestricted research, conducted at the researchers’ initiative. This approach will remain the linchpin of scientific policy for Inserm, which will make sure to maintain the level of allocations to the units, maintain set-up grants for newly recruited research fellows, enabling them to undertake their own research project, often following their return from a long post-doctoral period abroad, and continue its support for the Atip-Avenir programme. This spirit will also prevail in the design of more specific actions initiated by Inserm, such as the cross-disciplinary programmes, accelerators of technological research (ART) or new public health actions. On this last point, it will involve promoting scientific results as a support tool in making policy decisions related to health.


Objective 2: Support the translation of innovation into human health at economic, clinical and societal level

The area of biomolecular therapy development and exploitation of therapeutic targets nonetheless remains fragile, since it is a heavy user of financial resources, highly risky, and requires specialised and leading-edge expertise, while the potential returns are long-term or even very long-term. A specific project involving such innovations has yet to be undertaken with a view to strengthening the therapeutic or diagnostic applications of Inserm’s innovations, ensuring that Inserm maintains its high standing among the large international research institutions with respect to this development of therapeutic or diagnostic applications to the clinical stage, and encouraging the effective delivery of these innovations to the patient.


Objective 3: Strengthen the visibility and management of the infrastructures

Inserm intends to reinforce the clarity and coordination of its research infrastructures by developing its ability to ensure their supervision, mutual sharing and protection. The economic model (investment, operation, human resources) of the infrastructures as a whole must, in particular, be consolidated after a preliminary stage of defining Inserm’s strategic priorities and discussion with the partners.


Objective 4: Promote professional career paths and attractiveness

Inserm, a leading European operator in the biomedical research area, has a duty to implement an ambitious HR policy to maintain its position and meet the objectives of a research field that requires competency in an increasingly vast range of disciplines. To meet these challenges, the Institute hopes to adapt its employment policy to the demographic context: on the one hand, its ability to recruit staff with fresh skills via competitions will be limited in the near future; on the other hand, the reassignment of a significant number of positions from support to laboratory roles carried out in recent years is now clearly reaching a limit.

Schemes should therefore be established that will make it possible to simultaneously:

  • maintain and optimise recruitment;
  • mobilise the existing resources to the Institute’s strategic projects (supporting career paths and the potential for career development and mobility);
  • adapt the evaluation processes to changes in the researcher’s role;
  • optimise the career paths of contract staff, who are essential to the Institute’s research effort.


Objective 5: Contribute to the scientific strategy of the sites, optimise partnerships and simplify management to facilitate research

The reforms of recent years have enabled the emergence in our country of new models of scientific cooperation and working aimed at strengthening the synergies between the institutes of higher education and the research bodies. These reforms in the organisation of research in biology and health have led Inserm to evolve in order to participate fully in site policies, to jointly define the priorities, to support, together with the partners, the structuring of research in biology and health, and to ensure consistency between a national strategy and its local embodiments. Inserm advocates a principle of controlled participation in the numerous bodies established around these initiatives. First, we should talk in terms of programmes or projects rather than structures. Second, Inserm is involved in the structuring of the “biology/health” component of the sites, but does not have to participate in the general governance of the groupings or be a member of the Associations of Universities and Higher Education Institutions (Comues) (except when they are directing an Initiative of Excellence).


Objective 6: Increase Inserm’s role in the construction of the European Research Area

At European level, Inserm occupies a leading position in terms of coordination and participation in health-related collaborative projects under the 7th Framework Programme (FP7), and the Institute is one of the first two European recipients of ERC awards in the life sciences area. Inserm’s active participation in the construction of the European Research Area is well illustrated by the 434 FP7 projects managed by the Institute. To remain one of the major European actors in life sciences and health research, Inserm will implement a proactive, attractive and innovative policy. This policy has 3 main strands: to promote excellent targeted bilateral cooperation, to encourage the participation of Inserm teams in European programmes, and to spur influential actions within Aviesan and the Club of Associated Research Organisations (Clora).

Can we suppress the antipsychotic drug side-effects?

Since their development in the 1950s, antipsychotic drugs have been widely used to treat psychoses and neuropsychiatric disorders like schizophrenia. A debilitating side-effect of these drugs called parkinsonism limits their efficacy.Irvine scientists led by Emiliana Borrelli, Inserm research director at University of California and colleagues have discovered the key cellular mechanism that underlies the antipsychotic-induced parkinsonism – which includes involuntary movements, tremors and other severe physical conditions. These studies present evidence that will stimulate a targeted approach for the design of novel antipsychotics without side-effects. The results have been published in Neuron on July, 6th.


© Daniel A. Anderson/UCI

The researchers report that antipsychotics side-effects are due to blockade of the dopamine D2 receptor in a specialized type of neurons in the striatum, called interneurons. Blockade of D2 receptor in these neurons increases neurotransmitter signaling (acetylcholine) above threshold on neighbor neurons leading to motor abnormalities in rodents (catalepsy) which correspond to parkinsonism in humans. Catalepsy is marked by severe muscular rigidity and fixity of posture regardless of external stimuli. Indeed, in mouse studies, the Borrelli team discovered that removing D2 receptors in nerve cells (cholinergic interneurons) did not result in catalepsy in the mice upon antipsychotic treatment.


Borrelli said the importance of this study is twofold.

It clarifies a long-waited mechanism that allows to explain the motor side-effects of antipsychotic drugs and will help future design of drugs deprived of nasty side-effects. It also generates important information for combined therapies (using drugs that block D2 but also acetylcholine receptors) that should be used to improve the life of people treated for debilitating psychiatric disorders.”