"Modern Psychiatry": article in Public Service Review
This is a post-print version of the article that has been published in Public Service Review: science and technology, issue 7
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Hundreds of millions of people worldwide suffer from psychiatric diseases. The WHO estimates that 25% of the time that European employees spend away from work due to illness will soon be caused by mental disorders, posing a massive burden for afflicted patients, relatives and healthcare systems alike. For most of the 20th Century, psychiatric research had failed to live up to the challenges imposed by these numbers, but the last 20 years have witnessed a real ‘coming of age’ of psychiatry. After a history of scientific obscurity, the field has changed fundamentally: the neurobiological basis of mental disorders has moved into the focus, acknowledging that mental illnesses are disorders of brain circuitries that can be understood and treated based on neurobiological concepts.
Molecular genetics has been a key driving force in modern psychiatric research because essentially all psychiatric disorders have a major genetic contribution. Indeed, numerous recent studies – employing new technologies in genome analysis combined with very large patient cohorts, doublets or triplets of related patients, or exceptionally well characterised groups of patients – have yielded important insights into the genetic causes of mental disorders.
Most of the known disease-causing genetic variants have rather small effects because the corresponding disorders are caused by a combination of multiple disease-relevant genetic variations. In several cases, however, genetic variations with very large effects were found, some of them even causing monogenic heritable disorders where a single mutation inevitably leads to the corresponding illness. Particularly the latter are informative for further neurobiological analysis because monogenic heritable diseases can be modelled in genetically modified mice, which share most genes with man and can be studied with all modern neurobiological methods – unlike human patients.
GRAS – schizophrenia research at the Max Planck Institute of Experimental Medicine
Schizophrenia is one of the most frequent psychiatric disorders worldwide, affecting about 2% of the human population across all cultures. Patients suffer from so-called ‘positive symptoms’, such as hallucinations, and ‘negative symptoms’, such as cognitive deficits. Over the last three decades, multiple genetic perturbations were found to be associated with the development of schizophrenia, but how these variations cause the disorder is unknown.
To study the neurobiological basis of schizophrenia, scientists of the Max Planck Institute of Experimental Medicine in Göttingen, Germany, have established GRAS, the Göttingen Research Association for Schizophrenia. GRAS, which is spearheaded by Professor Hannelore Ehrenreich of the Max Planck Institute of Experimental Medicine, has generated a database of over 1,100 schizophrenia patients from all over Germany with 3,000 parameters per patient, including DNA and blood samples, biographic information, information on disease history, environmental risk factors, and comorbidities, as well as results of cross-sectional psychopathological, neuropsychological, and neurological examinations. The GRAS database is probably the most comprehensive information resource on living patients with schizophrenia worldwide.
Based on their database, GRAS scientists have developed the concept of ‘Phenomics-based Genetic Association Studies’ (PGAS) to characterise the contribution of genetic variants of candidate genes to particular schizophrenia symptoms. The PGAS approach assumes that single genetic variations alone do not ‘cause’ schizophrenia traits but co-determine, together with other genes, the specific clinical presentation of an individual suffering from schizophrenia.
In two recent studies, GRAS scientists discovered that the Complexin-2 and SK3 genes, which encode key proteins involved in nerve cell signalling, determine cognitive performance and decline in schizophrenia patients. This is an important step towards a better understanding of the neurobiology of schizophrenia, which shows that the GRAS database combined with the PGAS approach and other genetic analyses will change the field of schizophrenia genetics.
EUROSPIN – European Consortium on Synaptic Protein Networks in Neurological and Psychiatric Diseases
Brain circuits are made of nerve cells that communicate with each other through synapses. Synapses are complex cellular machines that mediate information transfer between nerve cells, where a sending cell releases messenger molecules that are sensed by a receiving cell. This process of synaptic transmission is controlled by hundreds of synapsespecific proteins.
That perturbations of synapse function must be at the core of many neurological and psychiatric disorders is illustrated beautifully by the fact that genetic perturbations causing psychiatric disorders often concern genes that encode synapse proteins. The corresponding disorders, which include illnesses as diverse as schizophrenia, autism, bipolar disorder, or major depression, are therefore synapse disorders, or synaptopathies.
The importance of the synaptopathy concept was also acknowledged by the European Commission, which issued, in 2009, the FP7-HEALTH call ‘Synaptopathies: Genesis, Mechanisms, and Therapy’. The call received massive attention in the European neuroscience community. The funds of about €12,000,000 were awarded to the EUROSPIN consortium, a group of 15 European and Israeli scientists and companies coordinated by Professor Nils Brose of the Max Planck Institute of Experimental Medicine in Göttingen, Germany.
EUROSPIN pursues a systems biology approach to study the role of synaptic protein mutations in psychiatric diseases and to develop new diagnostic tools and therapies. The concept is based on the constantly growing knowledge of disease genes, which the consortium complements with large-scale screens of mutant mice in order to identify and characterise disease-relevant mutations in synaptic proteins and corresponding mouse models. EUROSPIN researchers study disease-relevant synapse proteins, their interactions, and their roles in synapse physiology and neuronal network function. Focusing on mouse models of psychiatric disorders, EUROSPIN employs cutting-edge technologies in chemical biology, proteomics, protein interactomics, cell biology, molecular imaging, electrophysiology, and behavioural science. The aim is to understand the properties of molecular networks in synapses and to explain how single gene variants can result in a particular disease trait.
The many studies of EUROSPIN members illustrate that their aim of developing novel therapies for psychiatric disorders is within reach. One such study concerns autism. Here, the scientists have modelled heritable forms of autism in mice, which carry a mutation in the Neuroligin-4 gene that affects about 2% of autism patients and inevitably leads to autism spectrum disorders. These mice show autism-related changes in their social and communication behaviour and are currently being analysed, along with other genetic mouse models of autism, schizophrenia, and major depression, for functional synapse and neuronal network deficits. Based on the outcome of these analyses, the EUROSPIN scientists plan to develop experimental therapies in mice that will ultimately help affected patients.
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