Schizophrenia Studied at the Molecular Level in Rats

 

Researchers at the University of Southern Denmark, in a quest to understand schizophrenia on a molecular level, have performed studies on rats to identify several proteins that may play a role in the psychiatric illness. The study used rats that were dosed on Phencyclidine (a street drug otherwise known as PCP or “angel dust”) and state-of-the-art equipment to look at the proteins in the brains of rats who had received the PCP. Because it is difficult or impossible to tell if a laboratory rat is naturally schizophrenic, PCP is often used as a “psychotomimetic” in animal models to induce a schizophrenia-like state. Some of the symptoms and observable signs that can be compared between humans and rats are: diminished cognitive function: impaired attention, learning ability, and memory.

Schizophrenia is a persistent and chronic mental illness, affecting seven percent of the adult population, and characterized by what’s known as either positive or negative symptoms. The term “positive” refers to symptoms such as visual or auditory hallucinations, delusions, and disorganized thinking. Negative symptoms refer to deficits: persons with schizophrenia show what’s known as ‘flattened affect,’ or lack of emotion; also lack of motivation and withdrawal. Despite considerable research on the disease, its causes remain something of a mystery. It is actually considered by some to be a “syndrome” as it manifests itself quite differently between patients. Studies performed on identical twins proved that the cause of the disease was not purely genetic: if one twin had schizophrenia, the other was only 50 percent likely to have the illness.

To study schizophrenia at the molecular level, the researchers made use of 12 rats: six were injected with PCP, and the other six received an injection of saline (this is done to ensure that any differences found between the two groups of rats were not caused by the injection itself). At three time points: 15 minutes, 30 minutes, and 240 minutes after the injections, two rats from each group were sacrificed, and the temporal lobes of their brains were quickly frozen in liquid nitrogen. The brain tissue was then analyzed by mass spectrometry to see how proteins in the PCP-treated rat brains compared with the proteins in the negative control group of rats (i.e the rats who received saline injections). The mass spectrometer – the machine used in this study – analyzes the protein “signature” of the cells, sorting the proteins according to their mass-to-charge ratio.

According to Ole Nørregaard Jensen, of the University of Southern Denmark’s Department of Biochemistry and Molecular Biology, and one of the authors of the study reported on today, the group looked at 2604 proteins, of which 352 showed changes associated with the PCP injections. Apparently, the PCP turned proteins on or off inappropriately, setting off a chain reaction in the molecular network of the PCP-treated cells. Analysis of the results showed that PCP affects many processes in brain cells, including changes in calcium balance, which is extremely important to neuronal signaling; and changes in the cells’ ability to transport substances in and out of the cells. Other changes affected cellular metabolism and the cell’s skeletal structure, called the “cytoskeleton.”

Ole Nørregaard Jensen explained:

“These 352 proteins are what causes the rats to change their behavior — and the events are probably comparable to the devastating changes in a schizophrenic brain.”

Although rat and human brains are not completely equivalent, on a molecular level many of the proteins in the PCP-treated rat brains have sequences and functions that are similar (homologous) to proteins in the schizophrenic human brain. Now that scientists have a better look at the protein signature of cells in the PCP-treated rats, they can use this information to develop new medications to combat schizophrenia in humans.

By Laura Prendergast

Science Daily

Journal of Proteome Research

University of Southern Denmark

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