Immature Region of the Brain Could Underlie Some Brain Disorders

by Aalok Mehta

November 5, 2008

Underdevelopment of a specific region of the brain, the dentate gyrus, may contribute to schizophrenia and other psychiatric disorders, scientists from Japan have found. The discovery suggests that studying the dentate gyrus of humans could pave the way for new tests for many mental conditions.

The researchers, working with mice that show the symptoms of schizophrenia, discovered that their dentate gyrus, a part of the hippocampus associated with memory formation and mood, contains a large number of immature neurons. The researchers also found that humans with brain disorders show some of the same genetic changes in their brains as the mice, offering strong evidence that an underdeveloped dentate gyrus could contribute to brain diseases in humans.

Schizophrenia, bipolar disease and other mental disorders are currently diagnosed using only subjective criteria, study principal investigator Tsuyoshi Miyakawa, a geneticist at Fujita Health University, said by e-mail. But it’s likely that the disorders have different underlying physiological causes and therefore require different treatment. The new research is a first step toward identifying a specific biology—and perhaps a quantitative test—associated with some of these types of disorders.

However, the Japanese scientists are still unsure exactly why this area of the brain shows such a link to brain disease. “Here is my guess: The hippocampus is known to be involved in the replay of experience. Impaired function of the dentate gyrus could cause distorted replay of imaginary experiences,” helping disconnect people from reality, Miyakawa wrote.

The work appeared in the September issue of the open-access journal Molecular Brain.

Genetic effects

For their experiment, the researchers worked with adult mice known as alpha-CAMKII mutants. These animals show several schizophrenia- and bipolar-like behaviors, including memory problems, hyperactivity, aggressiveness and mood instability.

Miyakawa and his team found that neurons in the dentate gyruses of these diseased mice closely resembled still-developing neurons from the same regions of young mice. To study the effects of these underdeveloped areas, the scientists also conducted a genetic analysis. The test revealed that the schizophrenic mice expressed some 2,000 genes differently in their dentate gyri than normal mice.

The next step was studying whether these changes also occurred in people with brain diseases. The team could not test human brains directly for the presence of immature neurons, so they did the next best thing: check to see if human brains showed some of the same genetic disruptions as the mice.

Using 10 of the most prominent gene changes, the researchers found that 166 hippocampi, taken from deceased patients, appeared to fall into two distinct groups. One of these groups seemed to include people more susceptible to mental disorders, as it contained 16 schizophrenic patients (the other group included two such patients), along with one schizoaffective and two bipolar patients.

 “It is a good piece of basic science, and they are careful in their interpretation,” says Pat Levitt, a professor of pharmacology at Vanderbilt University who has extensively studied the developmental basis of neuropsychiatric disorders and was not involved with this study.

“The behavioral alterations they describe are exhibited in numerous psychiatric disorders, so these findings won’t mark a particular disorder,” he said. “Rather, the study does provide better rationale for more detailed studies on altered dentate gyrus function in human psychiatric disorders.”

Miyakawa’s lab now will try to find out what causes the neurons in the dentate gyrus to develop more slowly and then find ways to “rescue” them back to normal.