Researchers move closer to understanding the basis of a severe epilepsy and mental retardation

Jan 5 2006

Researchers at the University of California, San Diego (UCSD) School of Medicine took a step closer to understanding the basis of a severe epilepsy and mental retardation syndrome with work published in the January 5, 2006 issue of the journal Neuron.

Joseph Gleeson, M.D., Director of the Neurogenetics Laboratory at the UCSD School of Medicine and associate professor in the Department of Neurosciences, and his research team have developed a mouse model for a severe brain disorder in newborn children called lissencephaly, or "smooth brain."

"This is the first study to establish a link between the human and mouse disease that clearly shows we can model this condition in the lab," said Gleeson. "This study will allow us to begin to better understand what goes wrong in lissencephaly, and to use this mouse to figure out why children with this disease develop seizures and mental retardation."

It had been known that children with a genetic alteration in a gene called doublecortin suffer from epilepsy and mental retardation due to a defect in how the neuronal stem cells are positioned within the cerebral cortex. In the normal brain, neurons are born – adjacent to fluid-filled cavities deep within the developing brain – during the third and fourth month of gestation. Then they must migrate to reach their proper position within the six-layered cortex. When this migration is defective and neurons stop short of their proper destination, there is an absence of the normal grooves and ridges that characterize the brain in high mammals, including mice. Only four, instead of six, layers of cortex are formed, and the cerebral cortex of these patients lacks most or all of the hills and valleys of the normal human brain.

Gleeson and colleagues previously showed that mutations in the doublecortin gene account for nearly 20 percent of lissencephaly cases in humans. However, previous research by his lab and others yielded conflicting results about the nature of this condition, because researchers had failed to convincingly show in laboratory mice that a similar condition resulted from genetic alteration of the doublecortin gene.

In this study, UCSD team removed not one, but two genes from the mouse. This included both the doublecortin gene and a closely related gene with a similar structure known as doublecortin-like kinase. When both genes were removed, the laboratory mice showed features similar to those expected in human lissencephaly. Neuronal stem cells failed to send progeny cells to the correct position within the brain. As a result, the cerebral cortex did not show the normal six-layered structure characteristic of the mammalian brain.

"This study shows that brain development in mice is less susceptible to genetic deletions than in humans, because there is a redundant mechanism that fills in when just one gene is missing" said Gleeson. "The human brain is one of the most complex structures we know of, and evolution has been working hard to make the human brain over the past million years. It is not surprising that the human brain is more susceptible to genetic variation than the brain of a laboratory mouse."