Inflammation amplifies the effects of genetic risk variants for schizophrenia

People with schizophrenia have fewer
connections between nerve cells.
This is believed to be caused by genetic risk variations, which cause the brain's immune cells to over-eliminate nerve cell connections
.
Researchers at the Karolinska Institutet now report that Nature Communications in first-time patients saw elevated levels of proteins from associated risk genes and inflammation further increasing the expression of risk genes

In the brain in late adolescence, suboptimal connections between nerve cells are eliminated
normally.
Pruning these connections, so-called synapses, is important
for the development of functional neural networks.
However, people with schizophrenia have fewer
synapses.
A few years ago, researchers at Karolinska Institutet found in an experimental model that the elimination of synapses in people with schizophrenia has increased, which may be related to the genetic code for complement component 4A (C4A), a protein
involved in immune signaling.

The team has now developed a method
to measure C4A levels in cerebrospinal fluid.
In two separate cohorts, they observed elevated C4A levels in patients with first-episode psychosis, which would develop schizophrenia
a few years later.

"After examining genetic risk variants, we still observed elevated C4A levels," said Jessica Gracias Leikander, a doctoral student in the Department of Physiology and Pharmacology at Karolinska Institutet, who is the study's first author
.

The pro-inflammatory cytokines IL-1 β and IL-6 have previously been shown to be elevated in schizophrenia, and the researchers conducted new experiments in which they can demonstrate that these cytokines stimulate the expression of the C4A gene, and patients with high C4A levels also show high
levels of IL-1 β in the cerebrospinal fluid.
C4A levels are also associated
with synaptic density markers.

"This suggests that the effects we see in the lab are also related to the brain," said
senior author Carl Selgren Markowitz.

The researchers hope their findings will lead to more effective and personalized treatment strategies and become part of
the emerging precision psychiatry.

Carl Sellgren Majkowitz said: "The existing treatment is not individualized, but focuses on reducing psychotic symptoms
in patients who have already developed a disorder.
"