A molecular pathway which may impact on the development of schizophrenia has been identified by scientists from St. Jude Children’s Research Hospital while they were studying a rare genetic disorder.

The researchers, who reported their finding in the October 10th issue of The Journal of Neuroscience, say their discovery might pave the way for a new therapeutic target for treating schizophrenia. One of the problems with current treatments, apart from weight gain and some other undesirable consequences, is that some drugs for schizophrenia can actually structurally remodel the brain.

Schizophrenia is a devastating mental illness which is said to affect about 1% of adult’s worldwide. Signs and symptoms usually appear during a person’s late teenage years or early adulthood. The illness is characterized by a wide range of symptoms, including social withdrawal, memory problems, learning difficulties, delusions, and hallucinations.

Scientists have found it extremely difficult to identify the cause of schizophrenia, mainly because there is no single genetic mutation that is strongly linked to the disease. Studies have pointed towards many causes for the disease. In August 2012, an Australian team of researchers said they had strong evidence that schizophrenia may be an auto-immune disease.

Laurie Earls, PhD, and team in the laboratory of Stanislav Zakharenko, MD, PhD, at St. Jude Children’s Research Hospital, detected molecular changes that affect memory and are also present in patients with schizophrenia. They identified these molecular changes while studying a rare genetic disorder which is linked to schizophrenia risk.

The genetic disorder is called 22q11 deletion syndrome. Thirty percent of people with 22q11 deletion syndrome develop schizophrenia. Experts say that this genetic disorder is one of the strongest risk factors for schizophrenia.

The team had already identified alterations in nerve cells which led to deficits in the hippocampus in laboratory mice with the 22q11 deletion. The hippocampus is the learning and memory center of the brain.

In this latest study, Dr. Earls and team identified similar molecular changes in schizophrenia patients. They also located the gene that contributed to the nerve cell changes.

Carrie Bearden, PhD, an expert on 22q11 deletion syndrome at the University of California, Los Angeles, who was not involved in the study, said:

“This study makes some very important discoveries about the precise mechanisms underlying the learning and memory deficits seen in the genetic mouse model – problems that are a central part of the human disease. Pinpointing the specific gene involved is the first step toward developing targeted therapies that could reverse the cognitive deficits associated with schizophrenia, both in the context of this genetic mutation and the broader population.”

The team had already found in previous studies that cognitive dysfunction and unusual nerve cell communication were linked to higher levels of a protein that regulates calcium levels in some nerve cells known as Serca2. In mice with the 22q22 deletion, these abnormalities are only detectable with age.

The changes were being caused by the gene Dgcr8, the scientists found. Dgcr8 produces microRNAs that usually keep Serca2 in check. Without them the levels of the protein rise.

The scientists found that they could reduce higher Serca2 levels and reduce the cellular deficits linked to this genetic defect by adding these molecules back into the hippocampus of mice with the 22q11 deletion.

The authors wanted to determine whether what they discovered in the animal studies might also apply to humans with schizophrenia. They analyzed post-mortem brain tissue of schizophrenia patients.

The post-mortems showed that Serca2 levels were high in the patients with schizophrenia who did not have the 22q11 deletion.

Zakharenko said:

“These data suggest a link between the nerve cell changes in patients with the 22q11 deletion syndrome and those that occur in patients with schizophrenia. Serca2 regulation represents a novel therapeutic target for schizophrenia.”

Written by Christian Nordqvist