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

Schizophrenia is one of the most severe psychiatric disorders with onset of symptoms during early adulthood, followed in many cases by lifelong chronic illness that generates a high need for healthcare follow up, social difficulties and reduced quality of life. The causes of schizophrenia remain poorly understood and most drugs used in the therapy of the disorders have been developed serendipitously, and many patients do not achieve sufficient treatment effect. A core symptom of schizophrenia is cognitive impairment, which cannot be improved by current medications. Cognitive impairments are also seen in patients with anti-NMDA receptor (NMDAR) encephalitis. This represents a recently discovered form of autoimmune brain inflammation, in which autoantibodies against the glutamate receptor NMDAR induce psychotic symptoms that are indistinguishable from those seen in schizophrenia in addition to long-lasting cognitive deficits. Glutamate is one of the most important neurotransmitters in the brain that helps neurons communicate with each other. In the present project, we aimed to investigate the possible beneficial effect on schizophrenia of drugs enhancing NMDAR function, specifically D-serine and rapastinel. In the brains of young mice, we found a neuroprotective effect of rapastinel against cell death induced by the NMDAR antagonist MK-801. The effect was greater than that elicited by classical antipsychotics. At the network level, we found a hitherto unknown interaction between NMDAR agonists and antagonists, so that co-administration of rapastinel significantly increased neuronal activation triggered by MK-801 in brain regions important for schizophrenia, like the hippocampus, cingulate and retrosplenial cortex. The significance of these results for understanding the mechanisms underlying schizophrenia needs to be determined by future studies. At functional level we found that administration of D-serine in mice with deficient glutamatergic transmission, due to a missing component of the NMDAR, restored gamma oscillations in the brain. These preclinical results support the potential therapeutic efficacy of D-serine in schizophrenia, as gamma oscillations plays a key role incognitive functioning. The Norwegian part of the study provided new insights into the genetic architecture of schizophrenia and how it overlaps with other mental and neurological disorders, particularly epilepsy. Epilepsy is a neurological disorder characterized by excessive glutamatergic neurotransmission leading to seizures. The Norwegian studies found that a large part of the genetic vulnerability for epilepsy overlaps with both schizophrenia, cognitive abilities, and brain structures, indicating shared biological mechanisms. The identified overlapping genes were particularly linked to neurons. Further investigation of these genes may provide new insight into the overlapping mechanisms between these conditions, which can be used to create new and more effective medications. Furthermore, the findings may pave the way for precision psychiatry, in which individual genetic profiles can be used to personalize risk assessment and inform clinical decision-making and choice of medications. In addition to this, the Norwegian studies have shown that schizophrenia appears to exist on a genetic continuum across various psychiatric disorders, which to a large degree share genetic risk with each other. This is compatible with the high degree of overlapping symptoms and familial risk across psychiatric disorders, and provide new insights into their etiological relationships.

The consortium allowed a fruitful interdisciplinary interaction between investigators from different specialities as well as an exchange of knowledge, data and expertise on different methodologies. The overall project led to several publications and presentations at scientific meetings. Further it stimulated finding of new opportunities for future studies, for example including a translational metabolomic analysis. These preclinical results from the support the potential therapeutic efficacy of D-serine, that should be tested in the treatment of schizophrenia, since its actions may prove beneficial actions in restoring electrophysical properties which sustain perception and cognition. Thus, the project can lead to better treatment of people with schizophrenia. The project led to better understanding about the underlying genetic factors in schizophrenia and related traits. The findings also provide new insights into the origins and mechanisms of schizophrenia, which in general can lead to better treatment and care. The Norwegian part of the study provided new insight into the genetic architecture of schizophrenia and how this is overlapping with other mental and neurological disorders, particularly epilepsy.

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