Blocked Enzyme Reverses Schizophrenia-like Symptoms

The finding, reported in the March 20 issue of Cell, identified how a particular gene controls this brain enzyme. Better understanding of the relationship could lead to new drug treatments for schizophrenia, the severe brain disorder that affects about 1 percent of the population and is characterized by hallucinations, delusions, poor social and emotional functioning and disorganized thoughts.

The Picower research focused on a gene known as DISC1 (short for "disrupted in schizophrenia 1"), which was first identified in the 1990s by researchers studying the genetic makeup of a large Scottish family with mental and behavioral disorders. DISC1 has since been shown to help brain neuronal cells migrate to their correct positions and to help new neurons grow in the developing brain, but its role was not well understood.

Now, Li-Huei Tsai, the Picower Professor of Neuroscience in MIT's Department of Brain and Cognitive Sciences, and colleagues have shown for the first time that DISC1 directly inhibits the activity of a brain enzyme called glycogen synthase kinase 3 beta, also known as GSK3B.

Lithium chloride, the mood-stabilizing drug often prescribed for schizophrenia and bipolar disorder, also acts on GSK3B.

"This work for the first time provides a detailed explanation of how DISC1 functions normally in our brains," said Tsai, a Howard Hughes Medical Institute investigator and director of the neurobiology program of the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT.

"With this new knowledge of the DISC1-GSK3B interaction, one of the goals is to develop new drugs targeting schizophrenia, providing some hope that this devastating disease will be treated more effectively in the near future," she said.

Growing new neurons

Working with mice, Tsai and colleagues found that DISC1 regulates the growth of neural stem cells in both developing and adult brains. "During brain development, a fine-tuned mechanism regulates when neural stem cells divide and replenish their own population and when they turn into newborn neurons that will mature and grow appropriate connections with other neurons," Tsai said.

Tsai and colleagues found that halting expression of the DISC1 gene in neural stem cells causes them to stop dividing and prematurely turn into newborn neurons.

Eliminating DISC1 in adult mouse neural stem cells caused similar defects and produced behavioral changes such as hyperactivity, a symptom of schizophrenia in mice models of the disease. "Giving a chemical inhibitor of GSK3B to these mice completely reversed their abnormal behavior," Tsai said.

DISC1 works by directly inhibiting the activity of GSK3B, a target of the drug lithium. "It seems that DISC1 regulates the balance between neural stem cell self-renewal and turning into neurons, which impacts overall brain circuitry and can lead to compromised cognition and behavioral abnormalities," Tsai said. "Understanding the normal function of DISC1 in the brain could lead to new information on how schizophrenia arises due to genetic predisposition and environmental factors."

In addition to Tsai, co-authors are Picower Institute postdoctoral fellow Yingwei Mao; MIT Brain and Cognitive Sciences graduate student Xuecai Ge, Picower Institute postdoctoral associate Christopher L. Frank; Broad Institute researchers Jon M. Madison, Erin M. Berry, Takahiro Soda and Karun K. Singh; and colleagues at Massachusetts General Hospital, the Harvard-MIT Division of Health Sciences and Technology and the University of Washington School of Medicine.

This work was supported by the National Institutes of Health, the Stanley Center, the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the Human Frontier Science Program.