“NMDA receptor hypofunction revisited: Cellular mechanisms of psychosis in mouse models of NMDA receptor ablation”

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Genetic and immunological interference with the NMDA receptor (NMDAR) can drive endophenotypes reminiscent of psychoses. The underlying cellular and circuit mechanisms, however, remain poorly understood. In order to identify common mechanisms of circuit disruption, leading to psychotic behavior, we here propose to use an in vivo two-photon imaging approach to functionally characterize dedicated neuronal populations within the hippocampus, a region vital for cognition and hence the negative symptoms of psychoses. The impact of genetic ablation will be investigated in transgenic mouse models, in which the NMDAR is ablated either in excitatory neurons or in a specific type of interneurons. Immunological ablation will be realized through the application of autoantibodies targeting the GluN1 subunit, which in humans can cause a disease called anti-NMDAR receptor autoimmune encephalitis (AE). Novel mouse models to study the disease will be developed and subsequently tested in vivo. Upon the identification of an affected circuit element, e.g. a particular interneuron cell type, we will test cell type selective chemogenetic approaches to restore network function and ultimately rescue behavioral deficits. With these experiments we hope to advance our current understanding of the pathomechanisms that govern disrupted information processing in psychoses and identify novel therapeutic targets to selectively modify circuit function in dedicated brain areas.