Project: Microglial activation in Complement C4-stratified schizophrenic patients and in a mouse model of C4 overexpression

Acronym	microSCHIZ (Reference Number: NEURON-119)
Project Topic	Schizophrenia (SZ) is a prevalent and severe disorder but its treatment has suffered from a lack of progress. Recent genetic association studies identified SZ-associated genomic regions, many of which map onto the major histocompatibility complex. In particular, genetic variants conferring high expression of C4, a member of the classical complement cascade, are strongly associated with SZ. Microglial cells are part of the brain innate immune system and can be activated by immune challenges, in particular by C3a, downstream of C4 in the complement cascade. Microglial activation has been found in subsets of SZ patients. We also observed microglial activation in a novel mouse model of elevated C4 expression in the prefrontal cortex, along with neuronal alterations consistent with those observed in the brain of SZ patients. We hypothesize that high C4 expression activates microglia, thereby giving rise to SZ-associated neural endophenotypes. To examine this hypothesis, we propose a multidisciplinary approach involving clinicians and fundamental scientists. In humans, we will analyze the correlations between C4 genetics and disease severity, which will allow PET-Scan imaging in C4-stratified patients to analyze microglial activation. In parallel we will investigate, in a mouse model of high C4 expression, the interactions between neurons and activated microglial cells using PET-Scan, electrophysiology, in vivo 2 photon imaging, 3D electron microscopy and behavioral studies.
Network	NEURON Cofund
Call	Call for Proposals for Transnational Research Projects on Mental Disorders

Project partner

Number	Name	Role	Country
1	INSERM	Coordinator	France
2	INSERM	Partner	France
3	DZNE	Partner	Germany
4	University of Bern	Partner	Switzerland
5	University of Latvia	Partner	Latvia