Blocked Enzyme Reverses Schizophrenia-like Symptoms

March 20, 2009

Study results reveal that the gene DISC1—shown "to help brain neuronal cells migrate to their correct positions and to help new neurons grow in the developing brain"—directly inhibits GSK3B activity.

Study results from MIT researchers that were published in Cell reveal that the gene DISC1 (disrupted in schizophrenia 1)—shown “to help brain neuronal cells migrate to their correct positions and to help new neurons grow in the developing brain”—directly inhibits GSK3B (glycogen synthase kinase 3 beta) activity. With this knowledge, the research team was able to understand how the gene controls the GSK3B enzyme (a target of lithium chloride) and in turn determine that schizophrenia-like symptoms could be reduced with inhibition of the enzyme.

“This work for the first time provides a detailed explanation of how DISC1 functions normally in our brains,” said Li-Huei Tsai, the Picower Professor of Neuroscience in MIT's Department of Brain and Cognitive Sciences. “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.”

Tsai’s team studied mice to determine that DISC1 regulates neural stem cell growth in 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,” she said.

The cells stopped dividing and prematurely turned into newborn neurons when the researchers halted DISC1 expression. Similar defects were seen when DISC1 was eliminated in the neural stem cells of adult mice, also causing behavioral changes that were symptoms of the disease in mice. “Giving a chemical inhibitor of GSK3B to these mice completely reversed their abnormal behavior,” Tsai said. “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. 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.”

Click here to read the MIT press release for more on this story.