SOM researcher publishes findings that could lead to new treatment investigations for autism and schizophrenia
December 10, 2008
Alexander Gow, Ph.D.
Alexander Gow, Ph.D., associate professor of the Center for Molecular Medicine and Genetics, the Carman and Ann Adams Department of Pediatrics and the Department of Neurology, published the paper, “Claudin 11 Stops the Leaks,” in the Dec. 1 issue of the Journal of Cell Biology.
The brain, for the most part, can be divided into gray and white areas. Neurons are located in the gray area, and the white parts are where the neurons send their axons – similar to electrical cables carrying messages – to communicate with other neurons or muscles.
The white parts of the brain are white, Dr. Gow explained, because a cell type called oligodendrocytes makes a cholesterol-rich membrane called myelin that coats the axons. The myelin’s function is to insulate the axons, much like a rubber coating on an electrical cable. In addition, the myelin speeds communication along axons and makes that communication much more reliable.
Axons come in varying sizes, but generally the smallest are in the brain and the largest outside the brain, such as the sciatic nerve running down the leg. Dr. Gow said scientists have studied larger axons for decades to describe how myelin performs its function and have developed “excellent mathematical models.” However, he said, the models fail when applied to small axons in the brain.
Gow’s study involved destroying a gene in mice that encodes a myelin protein called claudin 11. The protein is a member of a family of proteins that function throughout the body to generate barriers, much like walls in a house compartmentalize rooms. The research showed that claudin 11 serves as a barrier in myelin in the brain to stop electrical current from leaking out of axons as they communicate with other cells. Small axons, which have a thinner sheath of myelin, are the most susceptible to the absence of the barrier. The lack of the barrier can slow electrical communication twofold. Large axons can be affected, but only marginally, because of their thicker myelin coating.
To determine whether claudin 11 was required for myelin’s insulating propensity, Dr. Gow compared electrical recordings from the optic nerve of wild mice and claudin 11 “knockout mice” -- animals in which the protein was suppressed. While claudin 11 deficiency did not change the appearance of the myelin sheath, he found its lack slowed electrical signals in neurons with small axons -- the thinner the sheath, the greater the effect. The protein added to myelin’s electrical resistance and prevented the “leaking” of communication current.
“To explain the results in the knockout mice, we developed a novel computer model of myelinated axons,” Dr. Gow said. “This model is based on previous models, but includes new features. Our model can account for the results we obtain. In contrast, previously developed models cannot account for the data. Our computer model enables us to show that the function of claudin 11 is to increase the electrical resistance of thin myelin, which improves the speed of electrical communication for small neurons.”
One of the most important areas of the brain where small axons are located is the corpus callosum, a structure that serves to connect the left and right halves of the brain. That communication allows humans to process sensory information such as sight and hearing, and facilitates appropriate interactions with the environment.
Patients with schizophrenia and other affective disorders are thought to suffer from brain disconnect –- the different parts of the brain don’t communicate with each other. Dr. Gow said this can be interpreted as neurons not sending signals to different parts of the brain or signals being sent but arriving too late because of myelin defects that allow “leaking.”
While Dr. Gow said the significance of the research in terms of immediately combating disease and disorders is speculative at this point, the findings may explain some of the symptoms for a number of neurological diseases, including autism, schizophrenia and other disorders.
“Currently, affective disorders are believed to involve defects in neurotransmitter function in the brain,” he explained. “However, the claudin 11 story suggests additional possibilities, specifically that defects in myelin can contribute to or cause symptoms.”
He pointed out that structural defects in myelin have been observed in neurological diseases via magnetic resonance imaging studies. These patients have also been found to display decreases in the speed of neuron communication. Patients with multiple sclerosis exhibit thinned myelin coatings in axons.
The abnormal expression of myelin proteins has been found in autopsy specimens from those suffering from schizophrenia. A strong candidate gene for schizophrenia, called neuregulin, is thought to be involved in regulating myelin synthesis as well as neurotransmitters in the brain. Another gene that regulates myelin synthesis is implicated in genetic forms of schizophrenia.
Patients with multiple sclerosis display neuronal loss and myelin abnormalities. In the disease’s advanced stages, much of the myelin damage is repaired, but the myelin is too thin. For small axons, this is equivalent to losing claudin 11. Multiple sclerosis patients, Dr. Gow said, can exhibit symptoms of schizophrenia, suggesting that thin myelin could be a contributing factor.
“While our study doesn’t suggest any treatments at this stage, it does suggest new directions of research that should be looked at in schizophrenia and other neurodegenerative diseases,” Dr. Gow said.