Synaptic autoimmunity in neuropsychiatric diseases

• Applicant: Professor Dr. Harald Prüß
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 239186027

Neuropsychiatric diseases resulting from auto-antibodies against neuronal surface proteins gained increasing scientific and clinical attention in recent years. The prototypical anti-NMDA receptor encephalitis is a relatively common form with characteristic clinical features including psychiatric symptoms, decreased levels of consciousness, epileptic seizures and dyskinesias. It is caused by highly specific autoantibodies directed against the NMDA receptor. Despite the favourable prognosis, most patients retain long-term deficits of attention, planning and memory. Besides these acute, severe changes of memory and behaviour in anti-NMDA receptor encephalitis, the same and related antibodies are now found in isolated symptoms such as schizophrenia-like psychosis and slowly progressive cognitive decline resembling primary dementia.There is compelling evidence for the association of a reduced number of NMDA receptors and the aetiology of several neuropsychiatric disorders. Animal models showed that disruption of NMDA receptors in postnatal mice could even much later result in symptoms that clearly resemble the deficits of patients with schizophrenia and NMDAR encephalitis. Own previous data showed that patient antibodies bind to NMDA receptors in a way that leads to reversible reduction of these and further synaptic receptors in the cell membrane of hippocampal neurons. In addition, immunosuppressive treatment in affected patients resulted in profound clinical improvement, parallel to reduction of antibody titers and increased glucose metabolism of certain brain areas.The complex molecular pathomechanisms of synaptic autoimmunity cannot be explored in patients, therefore preliminary data aimed at establishing a suitable animal model. In pilot experiments, actively immunized mice developed high serum titers of NMDAR antibodies. The here proposed research project should further validate the clinical phenotype of these animals and should answer the questions how even small levels of pathogenic antibodies result in clinical symptoms, whether the effect of autoantibodies includes further synaptic proteins, which brain areas are predominantly affected in vivo, whether experimental immunotherapies can lead to long-term loss of disease-related autoantibodies, and whether a transient exposure to these antibodies can result in delayed occurrence of neuropsychiatric abnormalities in memory and behaviour.Answers to these questions will likely reveal new fundamental scientific data about the causal relationship between autoimmunity and diseases of mind and memory, in particular schizophrenia and dementia. In this manner the present proposal will shed light on new therapeutic attempts and disease mechanisms for a group of neuropsychiatric disorders for which there is currently no specific therapeutic option.

• DFG Programme: Research Grants