Excessive activity of an immune system gene previously linked to schizophrenia reproduces the neuronal and behavioral aspects of the disease in mice, according to a new study published on January 14 in the open access journal PLOS Biology by Ashley Comer and Alberto Cruz-Martín of the University of Boston and their colleagues. The finding provides mechanistic support for the importance of the gene in the development of schizophrenia and may offer a new avenue for the development of therapy.
Previously it has been shown that genetic variants that increase the activity of the C4 gene, which encodes part of the so-called “complement” cascade of the immune system, increase the risk of schizophrenia in large genome association studies. However, the mechanism through which such variants could contribute to the onset of schizophrenia has not been clear because C4 has not been experimentally overexpressed previously.
During normal brain development, the complement is known to adhere to neuronal synapses and attract microglia (immune cells in the brain), which encompass synaptic material in the process known as “synaptic pruning.” When it is poorly regulated, this process can lead to abnormal connectivity in the brain.
Loss of synapse in the prefrontal cortex is a hallmark of schizophrenia, which led the authors to ask whether an overactive C4 gene could contribute to the development of schizophrenia through the erroneous regulation of complement-mediated synaptic pruning by microglia. When they overexpressed complement C4 in the mouse prefrontal cortex, they found an increase in the level of microglial envelope of the synapses, a reduced functional connectivity between neurons and alterations in the properties of neuronal membranes.
Schizophrenia is characterized by deficits in social cognition and social interactions, effects that often precede the development of psychosis. The authors found that juvenile mice with too much C4 complement reduced the time they spent searching for their mothers compared to control mice, and that adult mice spent less time than control mice interacting with new cage mates.
Together, these results suggest that the genetic association found between the increase in C4 gene activity and schizophrenia may be due, at least in part, to an inappropriate increase in synaptic pruning during brain development.
This critical window of development can provide the opportunity to intervene to alter the trajectory of the development of schizophrenia. “
Alberto Cruz-Martín, the principal investigator
While there are currently few approved medications that can block the complement system, it is an area of intense pharmaceutical research, and these findings are likely to generate even more interest in this approach.
Eat, A. L., et al. (2020) The increase in the expression of the C4 gene associated with schizophrenia leads to hypoconnectivity of the prefrontal cortex and the reduction of social interaction. PLOS Biology. doi.org/10.1371/journal.pbio.3000604.