New clues to schizophrenia come from mice, humans

Gene linked to schizophrenia in humans may provide new target for drug treatment

Improper signaling by a brain enzyme called calcineurin may contribute to the development of schizophrenia, according to new research by scientists at The Rockefeller University, Massachusetts Institute of Technology and Columbia University.

As a result of their studies of people with schizophrenia and a new mouse model for the psychiatric disorder, the researchers propose that calcineurin and other molecules that participate in the same cellular pathway may be new targets for the development of drugs to treat schizophrenia.

In the June 30 issue of Proceedings of the National Academy of Sciences Early Edition, the researchers report that they have mapped the location of the gene that produces one of the structural subunits of calcineurin to a region of human chromosome 8 already known to contain genes associated with schizophrenia.

“Based on our examination of 410 families with a history of schizophrenia and a new mouse model of schizophrenia, we have obtained several lines of converging evidence that show a disruption in calcineurin signaling plays a role in the development of schizophrenia,” says Rockefeller associate professor Maria Karayiorgou, M.D., senior co-author and head of the Laboratory of Human Neurogenetics at Rockefeller. “We believe these findings will reveal new possibilities for therapeutic intervention.”

Schizophrenia, a common severe mental illness that affects 1 percent of the population, is characterized by disordered thinking as well as deficits in emotional and social behavior. Karayiorgou’s research on the genetic causes of schizophrenia over the last decade has contributed to the identification of regions on two human chromosomes (8 and 22) that may harbor genes involved in a person’s susceptibility to this disease.

Last year, Karayiorgou and research colleagues in the United States and South Africa completed a systematic scan of a region on chromosome 22 called 22q11 and identified several genes as strong candidates for schizophrenia susceptibility.

In the current study published in PNAS, Karayiorgou collaborated with Susumu Tonegawa, Ph.D., at the Howard Hughes Medical Institute at Massachusetts Institute of Technology. Tonegawa and his colleagues have developed mice that are genetically altered to lack calcineurin only in the their forebrains. The forebrain controls cognitive, sensory and motor function, and regulates temperature, reproductive functions, eating, sleeping and the display of emotions.

These so-called “conditional knockout” laboratory animals previously were shown by Tonegawa to have impaired working memory, also known as short-term memory. In humans, working memory allows us to temporarily hold information – for example, remembering a telephone number just long enough to write it down or dial a phone – and is involved in such higher cognitive “executive” functions as planning, organizing and rehearsing.

In the “conditional knockout” mice, Tonegawa’s group also found behavioral abnormalities, including working memory impairment and social withdrawal, strikingly similar to those described for people with schizophrenia. (This finding is published in an accompanying article in the same issue of PNAS Early Edition.)

Based on the Tonegawa team’s findings, Karayiorgou and her Rockefeller colleagues, in collaboration with David Gerber, a research scientist on the Tonegawa team, conducted genetic studies of 410 families with histories of schizophrenia – 200 in the United States and 210 in South Africa. The Rockefeller scientists searched for genes encoding calcineurin or molecules that interact with calcineurin, focusing on those genes that mapped to areas on chromosomes known to be linked to schizophrenia susceptibility. The search for calcinuerin-encoding genes is ongoing, but for the findings reported in the new PNAS research paper, the scientists began their search from four genes, each of which is located on a different human chromosome. They analyzed the transmission of haplotypes (closely related variations of a gene that tend to be inherited together as a group) from parents to offspring with schizophrenia.

The search pinpointed one haplotype that had a strong association with schizophrenia susceptibility belonging to the gene PPP3CC, on human chromosome 8, very close to the area Karayiorgou and her colleagues originally identified several years ago. The PPP3CC haplotype was present in 38 percent of the parents’ chromosomes in the study and was transmitted to children with schizophrenia more times than would be expected by chance. The relatively high prevalence of the risk haplotype suggests that it may be contributing to the disease in a relatively large percentage of patients.

PPP3CC “codes” for the catalytic subunit of calcineurin, a molecule that belongs to a family of enzymes called phosphatases. Phosphatases and their molecular counterparts kinases control protein activity by acting as on-off switches in cellular signaling pathways. Kinases add phosphate chemical groups to proteins to turn on signals, while phosphatases remove phosphates and turn off signals.

Pharmaceutical companies are developing drugs designed to selectively target and block the function of kinases and phosphatases in signaling pathways for several diseases, and Karayiorgou believes her and Tonegawa’s latest research will open new possibilities for the treatment of schizophrenia.

“Our new findings, along with research by others in the field, suggest that PPP3CC and other genes in this region on human chromosome 8 may be contributing to schizophrenia susceptibility,” Karayiorgou says. “We are now thinking more in terms of pathways rather than one gene at a time. Different genes in a given pathway may be malfunctioning in different patients with the same end result. We are currently testing this hypothesis by extending our search in other genes in the calcineurin and other candidate pathways using high throughput screens.”

In addition to Karayiorgou, Tonegawa and Gerber, authors of the PNAS paper are Diana Hall and Sandra Demars, Rockefeller University; Tsuyoshi Miyakawa, Massachusetts Institute of Technology; and Joseph A. Gogos, Columbia University College of Physicians and Surgeons.

This research was supported in part by the National Institute of Mental Health, part of the federal government’s National Institutes of Health, the McKnight Endowment Fund for Neuroscience, the EJLB Foundation, and the New York City Council Speaker’s Fund.