The role of abnormal NMDA receptor-mediated transmission in specific neuronal populations in the post-adolescent onset of psychosis

• Applicant: Professor Dr. Dragos Inta
• Subject Area: Biological Psychiatry
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290792871

A vast body of evidence including the psychotomimetic effect of NMDA receptor (NMDAR) antagonists and the psychotic symptoms experienced by patients suffering from anti-NMDAR encephalitis support a causal role of NMDAR-mediated glutamatergic dysfunction in triggering psychosis. However, global NMDAR dysfunction induces numerous other (especially neurological) symptoms, whereas only specific, yet unknown neuronal populations may be implicated in psychosis. We aim to identify here by a pharmacogenetic approach in mice which neuronal populations are implicated in inducing NMDAR-mediated psychosis during late adolescence. For this purpose, we will generate 3 mouse lines with time- and cell-restricted tamoxifen-inducible ablation of NMDAR. In the first line, NMDAR will be deleted in neocortical/hippocampal parvalbumin (PV)-positive GABAergic interneurons, critical in generating oscillatory activity and in aberrant neuronal synchronization accompanying psychosis. A second line is represented by mice with inducible NMDAR ablation in ventral tegmental area (VTA) dopamine neurons, possibly implicated in dopamine dysregulation associated with psychosis. In a third line NMDAR will be ablated in neurons expressing erbB4, the receptor for the schizophrenia risk factor neuregulin 1. The erbB4-expressing neurons represent a larger population that comprises both PV-positive interneurons and VTA dopamine neurons, as well as other important modulators of striatal dopamine levels, the dopamine D3 receptor-expressing Islands of Calleja. All these neuronal populations are interconnected by multiple functional loops regulating oscillatory activity and dopamine function. The analysis will comprise multiple behavioural, neurochemical and electrophysiological assays. It will focus on analysis of changes in behaviour/cognitive function, synchronicity and dopaminergic dysregulation associated with psychosis. The final goal is to clarify the contribution of specific neuronal populations in psychosis and associated abnormalities, towards developing effective early therapeutic interventions.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Andreas Draguhn; Professor Dr. Peter Gass