Two Risk Factors for Schizophrenia Now Linked
A cause-and-effect relationship has been discovered between two already established biological risk factors for schizophrenia previously thought to be independent of one another.
The findings could eventually help scientists develop better drugs to treat the cognitive dysfunction of schizophrenia and possibly other mental illnesses.
Researchers have long studied the Disrupted-in-Schizophrenia 1 (DISC1) gene — a mutation strongly linked to the development of the disorder. In this study, researchers looked at the role this gene plays in glia cells known as astrocytes, a type of support cell in the brain that helps neurons communicate.
“Abnormalities in glia cells could be as important as abnormalities in neuronal cells themselves,” said study leader Mikhail V. Pletnikov, M.D., Ph.D, an associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.
“Most gene work has been done with neurons. But we also need to understand a lot more about the role that genetic mutations in glia cells play because neuron-glia interaction appears crucial in ensuring the brain operates normally.”
Besides the paranoia and hallucinations that plague sufferers of schizophrenia, many patients also have cognitive deficits, leaving them unable to think clearly or organize their thoughts and behavior.
Prior research has shown that one of the roles of astrocytes is to secrete the neurotransmitter D-serine, which helps transmit glutamate in the brain — vital for cognitive function. People with schizophrenia have decreased glutamate transmission.
It seems, Pletnikov said, that people with DISC1 mutations associated with the disorder are faster at metabolizing D-serine, which leads to a decrease in the crucial transmitter.
In clinical trials, other researchers are attempting to raise D-serine levels in people with schizophrenia to see if it will boost cognitive function.
In the new study, the Johns Hopkins researchers found that DISC1 is closely tied to the production of D-serine by the enzyme known as serine racemase.
The researchers discovered that DISC1 typically binds to serine racemase and stabilizes it. The distorted DISC1 in patients with schizophrenia cannot bind with serine racemase, and instead destabilizes and destroys it. The result is a deficiency of D-serine.
The researchers bred mice with the mutant DISC1 protein expressed only in astrocytes and, as predicted, the animals had lower levels of D-serine. These mice also displayed strange behavior “consistent with schizophrenia,” Pletnikov said.
For example, the mice showed sensitivity to psycho-stimulants that target glutamate transmission. By treating the mice with D-serine, the researchers were able to improve the schizophrenic-like symptoms. Mice without the DISC1 mutation in astrocytes had normal D-serine levels.
If drugs can be developed to enhance glutamate transmission in humans, patients with schizophrenia may experience better cognitive function. Pletnikov says a DISC1 mutation may also be a crucial risk factor in other psychiatric disorders as well.
“Abnormal glutamate transmission is believed to be present in patients with bipolar disorder, major depression and possibly anxiety disorders, so our findings could apply to other psychiatric diseases,” he said.
The study is published in the journal Molecular Psychiatry.
Source: Johns Hopkins
Pedersen, T. (2018). Two Risk Factors for Schizophrenia Now Linked. Psych Central. Retrieved on September 27, 2020, from https://psychcentral.com/news/2012/07/20/two-risk-factors-for-schizophrenia-now-linked/41895.html