Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Schizophrenia pathogenesis involves immune system dysregulation.
• High expression variants of the C4 gene, part of the complement system, are linked to schizophrenia susceptibility.
• The precise impact of elevated C4 expression on brain circuits is not well understood.

Purpose of the Study:

• To investigate how C4 gene overexpression affects neural circuits in the mouse prefrontal cortex.
• To explore the cellular and synaptic mechanisms underlying schizophrenia-associated endophenotypes.
• To establish a causal link between an immunogenetic risk factor and schizophrenia-related brain abnormalities.

Main Methods:

• In utero electroporation to overexpress C4 in mouse prefrontal cortex.
• Time-lapse two-photon imaging in vivo to observe dendritic spine dynamics.
• Electrophysiological recordings to assess synaptic function and neuronal excitability.

Main Results:

• C4 overexpression reduced glutamatergic input and spine density in juvenile and adult mice, mimicking schizophrenia.
• Deficits in dendritic spine formation and stabilization were observed in C4-overexpressing mice.
• Evidence of NMDA receptor hypofunction, altered AMPA receptor trafficking, and impaired GABAergic transmission was found.
• Reduced GABAergic transmission was linked to diminished release probability, lower GAD67 expression, and decreased excitability in parvalbumin interneurons.
• Working memory impairment was associated with these cellular abnormalities.

Conclusions:

• Elevated C4 expression causally links to specific cortical endophenotypes of schizophrenia.
• The study elucidates cellular mechanisms, including synaptic and network alterations, underlying C4's role in schizophrenia.
• Findings highlight the critical role of the immune system's complement component C4 in brain development and psychiatric disorders.