Department Researchers Find Higher Activity of the Immune-Regulating NF-κB Signaling Pathway in Schizophrenia

Schizophrenia is a devastating neurodevelopmental disorder, marked by changes in a person’s thinking, emotions, and behavior. A number of brain areas are affected in the illness, including a region called the prefrontal cortex that is important for cognitive control of behavior. A growing body of evidence suggests that the immune system is activated in the prefrontal cortex in schizophrenia, but it is unclear how this activation occurs or what role it plays in symptom generation. 

In order to better understand immune system changes in schizophrenia, Pitt Department of Psychiatry researchers recently used prefrontal cortex tissue from people with schizophrenia to conduct a large and carefully controlled study of a cellular signaling pathway called the nuclear factor-κB (NF-κB) complex that regulates several components of the immune system. 

“We found a really striking pattern of gene expression indicating that NF-κB complex activity is increased in the prefrontal cortex of people with schizophrenia. Our results point to NF-κB signaling as a key driver of cortical immune activation in the illness,” said the study’s lead author and Associate Professor of Psychiatry David Volk, MD, PhD. The new findings were published in the journal Biological Psychiatry.

The NF-κB complex is a group of proteins that binds to DNA and controls the gene expression of several components of the immune system. Dr. Volk and others have previously shown that there is increased gene expression of several of these immune proteins, as well as a few members of NF-κB complex, in the prefrontal cortex of people with schizophrenia. In the new study, Dr. Volk and colleagues used a technique called quantitative polymerase chain reaction (qPCR) to take a more detailed look at the NF-κB signaling pathway in the illness, quantifying the gene expression of 15 proteins that regulate the activity of the NF-κB complex in 62 pairs of schizophrenia and healthy control subjects. 

The researchers found that the gene expression of 12 of the 15 members of the NF-κB signaling pathway they looked at were elevated in the prefrontal cortex of subjects with schizophrenia. The increases in expression were relatively large, ranging from 24 to 71 percent. NF-κB pathway members with elevated gene expression in schizophrenia included the core proteins that form the DNA-binding complex as well as proteins that activate the complex. While the gene expression of most proteins that inhibit NF-κB activity by preventing the complex from binding to DNA were unchanged in schizophrenia, one showed higher expression in the illness. However, because the inhibitor is regulated by NF-κB activity itself, this finding is also consistent with higher NF-κB activity in schizophrenia.

In order to rule out antipsychotic drug exposure, the researchers then performed the same qPCR experiment on prefrontal cortex tissue from monkeys exposed to antipsychotics in a fashion that mimics how they are given to schizophrenia patients. Importantly, the team did not find changes in the gene expression of any of the 15 members of the NF-κB signaling pathway in the monkey tissue, indicating that the findings in schizophrenia subjects were not a consequence of antipsychotic use.

One unanswered question about immune activation in schizophrenia is when the immune system becomes activated. A number of epidemiological studies have found higher rates of schizophrenia among the children of women who were exposed to infections such as the influenza virus during pregnancy, suggesting that prenatal immune activation increases the risk of developing the disorder. In a final set of experiments, Dr. Volk and colleagues examined NF-κB pathway gene expression in two mouse models of immune activation, one in which the activation occurred in utero and another in which it occurred during adulthood. They found a gene expression pattern similar to that found in the schizophrenia subjects in the mice exposed to immune activation during adulthood, but not in the mice who underwent prenatal immune activation. These findings suggest that immune activation in schizophrenia is an on ongoing process and not a residual pathology related to an in utero insult.

“Taken together, our findings provide a pretty compelling line of evidence that higher levels of NF-κB signaling likely contribute to prefrontal cortical immune activation in schizophrenia,” said Dr. Volk. “Many of these NF-κB signaling components are preferentially expressed in microglia, the brain’s resident immune cells, so we are currently examining the role that microglia may play in schizophrenia.” 

The Role of the Nuclear Factor-κB Transcriptional Complex in Cortical Immune Activation in Schizophrenia
Volk DW, Moroco AE, Roman KM, Edelson JR, Lewis DA.

Biol Psychiatry, epub 2018, pii: S0006-3223(18)31629-9, doi: 10.1016/j.biopsych.2018.06.015.