Brain On Fire: Mechanisms Of Autoimmune Encephalitis Presenting With Psychosis, Seizures And Altered Levels Of Consciousness  Ewa Andrzejak , Frauke Ackermann; Christian Rosenmund; Harald Pruess; Craig-Curtis Garner (German Center For Neurodegenerative Diseases, Berlin, BERLIN Germany)   C19

Over the last decade, a growing number of psychiatric and central nervous system disorders have been linked to dysregulation of immune system and its autoreactive attack on the brain. These autoimmune encephalopathies present with a wide range of symptoms, from prominent psychiatric and cognitive manifestations, behavioral and personality changes, to severe seizures, abnormal movements and fluctuating levels of consciousness. Studies of patient cerebro-spinal fluid (CSF) revealed presence of autoantibodies against synaptic and neuronal surface proteins. In a population of patients these antibodies recognize a specific N-methyl-D-aspartate receptor (NMDAR), likely causing its cross-linking and subsequent internalization. Of note, the same receptor is a target of several known dissociative and anesthetic drugs, such as ketamine and PCP. Similarly, anti-NMDAR encephalitis patients often suffer initially from psychosis and dissociative states which then progress into reduced consciousness and coma. However, the antibodies' specific mechanisms of action and how they affect different levels of neuronal and brain function, which could contribute to altered consciousness observed in patients, are not fully understood. To address these questions, we generated recombinant monoclonal antibodies derived from CSF of a young women suffering from anti-NMDAR encephalitis. Here, using a combination of in vitro cell imaging assays and electrophysiological recordings, we aimed to investigate the effects of the antibodies on single neuron function and network activity. To this end, we observed that on a single cell level the antibodies selectively decrease NMDA currents, while at the same time dramatically increase activity of neuronal networks. Moreover, our recent data suggest that the antibodies may have differential effects on excitatory and inhibitory neurons within the cortical networks. Interestingly, similar mechanism has been proposed in the glutamatergic hypothesis of pathology of schizophrenia. Together, these data could provide more insights into the specific mechanisms of the disease as well as potentially shed more light on the neuronal mechanisms underlying psychoses.