Clinician Scientist-Programm 2024

Thema: "Cellular and circuit mechanisms underlying brain-wide functional hypoconnectivity in anti-NMDAreceptor encephalitis."

Zusammenfassung:
Anti-NMDA receptor encephalitis is a severe disease caused by autoantibodies directed against the GluN1 subunit of the NMDA receptor1. Patients affected by this disease typically first develop psychiatric symptoms including classical psychotic symptoms, followed by seizures and ultimately severe neurological symptoms with autonomic dysfunctions and reduced levels of consciousness1,2. Previous studies have established that autoantibodies cause an internalization of surface NMDA receptors and consequently a reduction of functional receptor density3–6. However, how this process influences neuronal circuits and,
through them, ultimately produces the characteristic symptoms remains still largely unknown. Human patients show pathologically reduced connectivity between various brain areas in functional MRI (fMRI) scans and impairments of specific connections correlate with specific symptoms7. The present application proposes to translate the macroscale level fMRI findings onto a microscale circuit level using a novel method for large-scale functional tracing of excitatory connections, called monoCaTChR8–10. These experiments will then be followed by more specific investigations of promising connections using in vitro patch-clamp recordings. Uncovering the underlying pathologies on a circuit level resolution will allow´testing of effects of pharmacological agents on specific targets and thus lay the basis for investigations of novel therapeutical approaches.