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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Understanding psychosis, cognitive impairment and motor symptoms induced by NMDA receptor dysfunction: mechanisms to prevention and therapy

Alternative title: Forståelse av psykose, kognitiv svekkelse og motor symptomer indusert av NDMA-receptor dysfunksjon: mekanismer til forebygging og terapi

Awarded: NOK 2.5 mill.

Severe mental disorders begin in young adulthood, followed in many cases by long-term symptoms that require medical treatment and social problems. The disease mechanisms of severe mental disorders such as schizophrenia are unclear, and most drugs have been developed without empirical evidence. The core symptoms, such as psychosis, mood disorder and cognitive dysfunction, are present across different diagnostic categories. Furthermore, psychiatric disorders are associated with an increased incidence of epilepsy. However, the causal mechanisms underlying these conditions are poorly understood. The overall goal of this project is to elucidate the overlapping genetic architecture of associated traits and comorbid disorders with psychiatric illness to gain a better understanding of their comorbidity and shared clinical features. In particular, we examine overlapping genetic risk factors between schizophrenia, compared with the psychiatric disorders; bipolar disorder, major depression, Attention Deficit Hyperactivity Disorder (ADHD), and Autism Spectrum Disorder. We will use data from large genetic studies to detect genetic overlap using modern statistical methods and quantify the unique genetic architecture of each disorder, as well as overlapping relationships between the disorders. We aim to fill knowledge gaps about the genetic background of these disorders and to inform about common disease mechanisms, disease etiology and pathophysiology. The ultimate goal is to better understand mechanisms for mental disorders that in the future may form the basis for the development of better drugs. We have made progress in gene discovery in schizophrenia, both as part of the large international Psychiatric Genetics Consortium (PGC), and more focused studies. The latest PGC schizophrenia study, which includes over 65,000 people with schizophrenia and over hundred thousand controls, showed a large number of new gene variants in schizophrenia, and showed that communication between nerve cells (synaptic biology) is implicated in the disease. Furthermore, it showed the significant genetic overlap with bipolar disorder and depression. We also conducted a study in which we discovered genetic overlap between brain structure (measured by MRI) and schizophrenia. This suggests that genetically determined variation of the brain's gray matter (cortex) appears to be associated with the development of schizophrenia. This suggests that the disease mechanisms of schizophrenia arise from many, small changes in brain function. Furthermore, it showed the significant genetic overlap with bipolar disorder and depression. We have carried out several studies in which we have characterized genetic overlap between independent symptom profiles in mental health. Some of these are also genetically correlated with schizophrenia.

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Despite intense basic and clinical research in the last decades, the pathophysiological mechanisms underlying schizophrenia are still insufficiently understood, leading to a lack of innovation in its treatment. Moreover, especially those abnormalities associated with the chronic course of the disease, i.e. cognitive impairment and negative symptoms (blunted affect, social withdrawal), are still poorly alleviated by current antipsychotics. Extensive evidence suggests a glutamatergic component in schizophrenia. The recently described anti-NMDA receptor encephalitis induces psychotic symptoms largely indistinguishable from schizophrenia, including motor symptoms like catatonia-like states seen in severe forms of schizophrenia. Here we aim to determine in an interdisciplinary approach the possible beneficial effect of drugs enhancing NMDAR agonists, mainly D-serine, but in mouse models also sarcosine and rapastinel (Glyx-13), in alleviating behavioral abnormalities/clinical symptoms associated with NMDAR dysfunction in specific mouse models, as well as morphological alterations (focusing especially on hippocampal damage) and functional impairment (with focus on dysconnectivity and alterations of brain oscillatory activity) in patients with schizophrenia. We will investigate the effect of NMDAR enhancing strategies both in prodromal and chronic, therapy-resistant schizophrenia, determining as well possible genetic determinants of the therapeutic response. Our project has a central translational component: we will analyze, based on hints from literature, two genetically modified mouse lines with alterations in NMDAR in selective neuronal populations expressing the schizophrenia risk factor erbB4 or a specific NMDAR subunit, GluN2D. Data obtained in the animal models will be thoroughly compared and analyzed with those resulting from the clinical trials in all disease-relevant dimensions mentioned. Our ultimate goal is, by identifying novel molecular and cellular substrates

Funding scheme:

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering