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.”

A study from Inserm, Paris Descartes University and Sainte Anne Hospital suggests that anorexia nervosa might not be explained by fear of gaining weight, but by the pleasure of losing it… and that the phenomenon might be genetically influenced. Published in Translational Psychiatry, this study, directed by Prof. Gorwood, head of the Clinic for Mental and Brain Diseases, challenges the notion of fear of weight gain in anorexia patients.

(c) Fotolia 

Often associated with major psychological distress, anorexia nervosa is an eating disorder that mainly affects girls and young women. Diagnosis is based on three international criteria: restriction of food intake leading to weight loss, a distorted perception of weight and body, and an intense fear of becoming fat.

Although there is no pharmacological treatment, Prof. Philip Gorwood’s team has focused on these clinical criteria. As the researcher explains: “When research is going nowhere, it is important to call into question the criteria at the very root of the disorder. We have therefore re-evaluated the last criterion, although it is quite prominent in patient discourse, by assuming that it is a mirror image of what is really involved, i.e. a reward for losing weight. We established the postulate that patients felt pleasure at becoming thin rather than fear of becoming fat.”

So as not to be influenced by patients’ discourse and analysis of their eating disorders, the researchers used a “skin conductance test,” which measures the subject’s sweating rate when exposed to various images. The emotion caused by certain images actually leads to a rapid and automatic increase in sweating.

The researchers showed images of people of normal weight or overweight people to 70 female patients consulting the Clinic for Mental and Brain Diseases (CMME) of Sainte Anne Hospital. For these patients, of varying weight and with different degrees of disease severity, viewing these images caused much the same reaction as in healthy subjects. Conversely, when looking at images of thin bodies, the patients showed positively evaluated emotions, whereas healthy subjects had no particular reaction.

Anorexia nervosa is a highly heritable disorder (70%). One of the genes most often associated with anorexia nervosa codes for BDNF, a factor involved in neuron survival and neuroplasticity. In patients with anorexia nervosa, the study indicates that the increase in sweating experienced when viewing images of thin bodies is explained by the presence of a specific form (allele) of the gene in question. This result was confirmed after examining potential confounding variables such as weight, type of anorexia or duration of the disorder.

The conclusions of this work:

-support the genetic approach as a different way of addressing the key symptoms of anorexia nervosa;

– orient research toward reward systems rather than phobic avoidance;

– finally, they suggest that certain therapeutic approaches, such as cognitive remediation and mindfulness therapy, might have a clear beneficial effect on this illness.

For the first time, scientists in the Center for Interdisciplinary Research in Biology (CNRS/INSERM/Collège de France) have produced direct evidence that the long-term storage of memories involves a dialogue between two brain structures, the hippocampus and cortex, during sleep; by enhancing this dialogue, they succeeded in triggering the consolidation of memories that would otherwise have been forgotten. This work is published in Nature Neuroscience on 16 May 2016.

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Since the 1950s, the principal theories on memory have posited that such traces are initially formed in the hippocampus and then gradually transferred to the cortex for long-term storage. Although supported by numerous experimental studies, this hypothesis had never yet been directly verified.

In order to prove it, the scientists first recorded the activity of the hippocampus and cortex during sleep. They found a correlation between the oscillations observed in these two structures: when the hippocampus emitted sharp wave-ripples, the cortex in turn emitted delta waves and spindles like a series of questions and answers. To establish a link with memory, the scientists then trained rats to memorize the position of two identical objects in a room. During testing the next day, one of the objects had been moved and the rodents had to determine which one. Those that had spent 20 minutes in the room on the first day passed the test, while those that had only been there for three minutes failed. This difference was also reflected in the hippocampal-cortical coupling during sleep just after the initial exploration: coupling was more visible in rats that passed the test the next day. It was then necessary to prove that this was indeed the cause of memorization.

The scientists then developed a system for real-time detection of hippocampal sharp wave-ripples and immediate triggering of cortical delta waves and spindles, or in other words to generate coupling between these two structures on demand. They applied this system in rats that had been trained for just three minutes the first day, and were therefore not expected to remember the position of the objects the next day: these rodents passed the test perfectly. By contrast, if a variable delay was introduced between the hippocampal and cortical waves, the effect disappeared.
To better understand the mechanisms at play, the scientists also recorded cortical activity during learning, sleep and the test. They observed that selected neurons changed their activity in the context of coupling during sleep, and that the next day the cortex responded to the task by becoming more active in the vicinity of the object that had been moved.

By demonstrating the mechanisms underlying long-term memorization, this work may shed new light on certain memory disorders in humans. It might thus be possible to envisage overcoming certain memory deficits if they result from the same mechanism as that studied here. However, the ethical issues related to these techniques will need to be addressed and methods will have to be refined to enable selective action on the memories that need to be enhanced, before any clinical application can be envisaged. The team is now set to elucidate the dialogue between the hippocampus and cortex, notably when several memories need to be remembered, or not.

Individual small RNAs are responsible for controlling the expression of gonadoliberin or GnRH (Gonadotropin-Releasing Hormone), a neurohormone that controls sexual maturation, the appearance of puberty, and fertility in adults. This has just been demonstrated by the “Development and Plasticity of the Neuroendocrine Brain” team led by Vincent Prévot, Inserm Research Director (Jean-Pierre Aubert Research Centre, Lille). The involvement of microRNAs, transcribed from DNA, occurs around birth, and marks a key step in postnatal development. Failure of these microRNAs to act leads to the disruption or even total cessation of GnRH production by the hypothalamic neurons that synthesise it, and hence to infertility. In the most serious cases, sterility may result. Details of this work in mice are published in the 2 May 2016 issue of the journal Nature Neuroscience.

(c) Inserm/Prévot Vincent

Images showing the expression of the neurohormone GnRH (green) by the hypothalamic neurons that synthetize it in mice in which GnRH neurons have been genetically tagged by the Tomato gene (gene coding for a red fluorescent protein).

Reproductive function is determined by events that take place in the brain. Gametogenesis (the production of spermatozoa and oocytes) and the secretion of hormones by the ovaries and testes are heavily dependent on the hypophysis, a small gland located below the brain, to which it is connected by a capillary network. The latter is in turn controlled by a glandular “orchestra conductor” located at the base of the brain, the hypothalamus. During postnatal development, activation of a small number of highly specialised neurons (the GnRH neurons) in the hypothalamus leads to the synthesis of a hormone, gonadoliberin or GnRH (Gonadotropin Releasing Hormone), and this process leads to the appearance of puberty.

This step, known as “mini-puberty” constitutes the first activation of the reproductive axis by the brain. It occurs between the first and third months of life of the infant, and is important to the correct course of sexual maturation*. At puberty, GnRH stimulates the synthesis by the hypophysis of other hormones, which in turn enter the bloodstream to promote the growth of the gonads (ovaries and testes), and to subsequently ensure reproductive function.

The appearance of puberty remains one of the greatest scientific enigmas of the 21^st century. In the last 30 years, the discovery of mutations in various parts of the genome in patients with disorders of puberty has made it possible to identify some genes involved in this process.

However, physicians and scientists believe that these genes are responsible for only a third of the disorders of puberty encountered in patients. The discovery of the involvement of microRNAs opens up considerable prospects for the medical management of these patients, from both a diagnostic and therapeutic point of view.

MicroRNAs are small non-coding RNAs transcribed from our DNA. In contrast to messenger RNAs (mRNA), they are not translated into proteins. Because of this, microRNAs are not part of the “coding genome,” but constitute what some people call the epigenome. Regulation of gene expression, e.g. expression of the GnRH gene, by microRNAs is therefore considered “epigenetic” regulation.

Research conducted in mice by Vincent Prévot’s team shows that birth induces a radical change in the expression of microRNAs in the hypothalamic GnRH neurons. This modification of the microRNA expression profile is essential to the inhibition of the expression of transcription factors (proteins that activate or inhibit gene expression) that have a repressive effect on GnRH expression. This inhibition of inhibitory factors allows increased production of GnRH, which is indispensable to infantile and juvenile sexual maturation, and the occurrence of puberty. Indeed, in the absence of microRNAs, the expression of transcription factors that inhibit GnRH expression increases, and leads to the extinction of GnRH synthesis in the brain, leading to the arrest of sexual maturation, absence of puberty, and complete sterility in adult individuals. Analysis of the GnRH gene in humans shows that analogous phenomena might occur in our own species. The mechanism elucidated by this team might therefore explain the absence of puberty and the occurrence of infertility in some patients for whom no mutation or polymorphism (variation in DNA sequence) has been identified in the coding genome.

(c) Andrea Messina/Inserm

In terms of diagnosis, the study carried out by Vincent Prévot’s team in Lille shows the interest of analysing DNA segments from which microRNAs are transcribed, as well as the genome segments that encode their binding sites on the target genes.

“The work published today shows the importance of studying the genome sequences that will be transcribed into mRNA molecules, to which microRNAs bind in order to regulate their translation into protein,” add the researchers.

From a therapeutic standpoint, the interaction of microRNAs with the genes they regulate may be prevented or mimicked by the administration of small analogous molecules, for which the study done by Vincent Prévot’s team provides proof of concept.

This research received financial support from the French Medical Research Foundation (FRM).   

* This mini-puberty is seriously compromised in premature infants, who are more likely to develop disorders of puberty and adult infertility than infants born at full term.

A research team from Paris Descartes University, Inserm and Sainte-Anne Hospital, led by Professor Marie-Odile Krebs, has demonstrated that epigenetic modifications accompany the onset of a psychotic episode in a cohort of young at-risk people aged 15–25 years. These modifications compromise systems for responding to oxidative stress and inflammation. Through this new work, the researchers have shed new light on this disease, for which the main biological explanation, before now, was based on disruption of dopamine secretion in the brain.

The study was published in Molecular Psychiatry on 26 April 2016

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Psychotic disorders preferentially affect a young population, and have a major social impact. Several years before the onset of a true psychotic episode, certain changes in behaviour (isolation, aggressiveness), or certain non-specific (anxiety, problems with concentration or sleep) or more specific symptoms (perceptual abnormalities, fixed ideas, etc.) are generally present. Certain assessment tools have make it possible to define “at-risk mental state” criteria. Approximately one third of people with an “at-risk mental state” will develop a psychotic disorder within three years. There is therefore strong clinical relevance in understanding the physiopathological mechanisms that accompany this change, in order to better define monitoring strategies and, especially, therapeutic interventions.

To study the onset of psychosis, the team of researchers adopted an original approach: they studied modifications in the methylation profile[1] (measured using a blood sample) of young at-risk subjects (ICAAR cohort), monitored for a period of one year. They compared the profiles of individuals who had experienced a psychotic episode with profiles of those who had not become ill. Their conclusions indicate that epigenetic modifications are involved in the onset of a psychotic episode. The modifications preferentially occurred in promoters of genes involved in protection against oxidative stress, in axonal guidance and in the inflammatory response.

Dynamic epigenetic changes accompany the onset of psychosis

The study was carried out on 39 young subjects, 14 of whom developed a psychotic transition in the year following their entry into the cohort. Analyses were concerned with over 400,000 methylation sites, distributed throughout the entire genome (also known as the “methylome”). They included the temporal dimension (comparison before and after the onset of psychosis), but also required the constitution of an appropriate control group (made up of young people who sought care and/or psychological support, but who did not meet the criteria of at-risk subjects). From the start of monitoring, people who went on to develop psychosis showed hypermethylation of the GSTM5 gene promoter[2]. During monitoring, hypomethylation of the GSTT1 gene promoter was observed, and hypermethylation of the GSTP1 gene. These three genes protect against oxidative stress. Other significant modifications were found in genes associated with inflammation and axonal guidance of neurons.

Approaches to developing molecular tools for early detection and targeted therapeutic agents

These results will lead to improved understanding of the biological upheavals that accompany the onset of psychosis. Until now, disruptions in dopamine secretion at brain level were the main physiopathological explanation for psychosis. With the help of these new data, its onset may be linked to an inflammatory or oxidative stress that disrupts the balance (homeostasis) that has already been weakened by a genetic, environmental or neurodevelopmental vulnerability. These results pave the way to the development of tests for the early detection of the illness and monitoring of its progress in these at-risk populations, since this disruption of homeostasis can be easily detected via blood samples, on a repeat basis if necessary. They also point to new therapeutic strategies aimed at preventing psychotic conversion.

[1] Epigenetic modifications are represented by biochemical tags present on the DNA. They do not modify the DNA sequence, but do, however, induce changes in gene activity. The best characterised are methyl groups (CH3: one carbon atom and three hydrogen atoms) attached to the DNA.

[2] A member of the glutathione transferase family, this gene encodes key enzymes that protect against oxidative stress.

Treatments available for glioblastoma—malignant brain tumors—have little effect. An international collaboration[1] led by the Laboratoire Neurosciences Paris-Seine (CNRS/ INSERM/UPMC)[2] tested active ingredients from existing medications and eventually identified one compound of interest, prazosin, on these tumors. Not only did it seem to be effective in this type of cancer, but it also acted on a signaling pathway that is common with other cancers. These promising findings are available online (advance publication) in EMBO Molecular Medicine.

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Turning old into new is what recycling is all about—and what is being attempted by an international collaboration of research scientists coordinated by Marie-Pierre Junier and Hervé Chneiweiss at the Laboratoire Neurosciences Paris-Seine (Paris). The researchers chose to study the most common malignant tumors that develop from brain cells, glioblastomas, which represent the fourth most frequent cause of cancer deaths among adults and the second in children. This is due to the inefficacy of current treatments. Indeed, a glioblastoma can resist treatment and reawaken from a very small number of tumor cells called glioblastoma-initiating cells (GIC). It is these cells—whose characteristics and properties resemble those of stem cells—that were targeted in the study.

Rather than trying to discover new compounds, the team opted for repositioning existing drugs. In other words, they tested a collection of substances used for so long to treat other conditions that their patents have now fallen into the public domain[3]. This method makes it possible to develop new active ingredients cheaply and very rapidly. Twelve hundred compounds were thus tested on normal human neural stem cells and on glioblastoma-initiating cells from different aggressive tumors.

Twelve of these compounds showed a toxic effect on GIC—and none on the normal neural stem cells. The most effective was prazosin. Tested in mice carrying glioblastoma-initiating cells, prazosin significantly reduced the size of tumors and prolonged survival of the mice by more than 50%.

This compound, which has been used for many years to treat hypertension, is an alpha-adrenergic receptor antagonist. The researchers nonetheless made a surprising finding: glioblastoma-initiating cells are devoid of these receptors. The compound therefore acts via an “off-target” mechanism, or in other words through another pathway than standard interaction. The scientists thus identified an intracellular signaling molecule, PKCδ, which is over-expressed in GIC when compared with normal neural stem cells. In the presence of prazosin, it is only cleaved in GIC, which leads to their death.

Clinical trials will be initiated this year to confirm these findings. If they are conclusive, the compound could rapidly be introduced to complement existing therapies and improve the management of patients with brain cancer. Already, the scientists have discovered that other cancer cells display altered PKCδ signaling, including those in colorectal, pancreatic and liver cancer. Understanding the mechanism of action of prazosin may therefore pave the way for the development of new potential treatments for other cancers.

[1] Including scientists from the Laboratoire d’Innovation Thérapeutique (CNRS/Université de Strasbourg), the Stanford University Institute for Stem Cell Biology and Regenerative Medicine (USA) and the Instituto Estadual do Cérebro Paulo Niemeyer in Rio de Janeiro (Brazil).

[2] This laboratory forms part of the Institut de Biologie Paris-Seine.

[3] Pharmaceutical compounds are protected by a patent for 20 years after their discovery. Because of the length of the clinical trials that are necessary before a drug can be put on the market, the duration of their patent protection does not normally exceed 10-15 years after a Marketing Authorization (MA) is granted.

A team coordinated by Prof. Emmanuel Flamand-Roze from Pitié-Salpêtrière Hospital, AP-HP, has tested, at the clinical investigation centre of the Brain and Spine Institute (Inserm /CNRS/UPMC) , the efficacy of zonisamide, a drug currently used to treat certain forms of epilepsy, in 23 patients with a rare disease of the nervous system, myoclonus-dystonia. The promising results from this trial, which was funded by AP-HP (the Paris Public Hospitals), are the subject of a publication in the journal Neurology on 6 April 2016.

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Myoclonus-dystonia is a rare disease that results from poor control of movements by the brain, leading to abnormal muscle contractions. It features two types of symptoms: jerky muscular movements (myclonus), and an abnormal posture of some parts of the body (dystonia). The unpredictable muscular jerks that accompany every one of the patient’s movements are the most disabling symptom. They are usually strongest in the upper limb and neck regions. The mobility problems associated with this disease can seriously impede the activities of daily living. These highly visible disorders often lead to stigmatisation, loss of self-esteem, and social withdrawal among patients. There is presently no effective drug for this disease. There is, however, a neurosurgical treatment that gives good results, but it is invasive, and restricted to severe forms of the disease.

The scientific team, made up of physicians and researchers, conducted a randomised, double-blind, placebo-controlled trial, to test the efficacy of zonisamide in 23 patients with myoclonus-dystonia. Zonisamide is a drug that has been used in Europe for the last ten years to treat certain forms of epilepsy. It is well tolerated by most patients who use it for this purpose.

The results of this trial show that zonisamide brings about a highly significant reduction in the myoclonus and associated disability. The patients’ dystonia is also alleviated by this treatment.

“This is the first trial to demonstrate the efficacy of a drug against this disease,” explains Prof. Flamand-Roze. “Zonisamide may therefore be offered to patients with mild and moderate forms of myoclonus-dystonia, and to all patients who choose not to have, or who cannot have neurosurgical treatment.”