September 25, 2000
La Jolla, CA – Salk scientists have obtained the first snapshot of how gene behavior varies among mammalian brains. The study employed “gene chip” technology to simultaneously compare the activities of approximately 13,000 genes in two inbred strains of mice.
Because the strains differ in their susceptibilities to seizures – and their genetic responses to seizures were found to differ as well – the approach may have implications for treating human epilepsy.
“There’s a tremendous potential with ‘chip studies’ to look at many genes at once,” said Carrolee Barlow, Salk assistant professor and senior author of the study, which appears in the current issue of the Proceedings of the National Academy of Sciences. “We can get a profile of what genes are active, where in the brain they’re active and under what conditions they’re turned on or off.”
Barlow added: “We expect this technology will make it possible to pin down the genetic components of complex traits like epilepsy, alcoholism and mental illnesses such as schizophrenia.”
Predisposition to these conditions is thought to depend upon specific combinations of genes, and previously available techniques could examine only individual genes or small numbers of genes at once. The “chip” technology affords scientists the opportunity to track large numbers of genes and ferret out subtle patterns.
In their study, Barlow and her colleagues used strains of mice known to differ in a number of neurobehavioral traits including their overall activity levels, responses to learning, sensitivity to environmental stimuli and propensity for voluntary alcohol intake.
The investigators compared gene activity across six distinct regions of the brain. Of the more than 13,000 genes canvassed, 73 were found to vary between the two strains in one or more brain areas.
“The proportion of varying genes is quite small,” said Rickard Sandberg, co-first author of the study. “We had to take many precautions to be sure the differences we saw were significant and not due to fluctuating circumstances.”
These precautionary measures included using only male mice to eliminate sex-based differences, removing potential sources of stress and always surveying gene activity at the same time of day.
After establishing a baseline of gene differences, the team assessed the genetic responses to seizure. The strains surveyed, C57BL/6 and 129SvEv, recover from drug-induced seizures to different degrees. The sensitive 129SvEvs experience extensive cell death in the hippocampus, a region of the brain important for learning and memory. The more robust C57BL/6s show little cell death.
The Salk-led team monitored gene activity in the brains of both strains following seizures induced by treatment with pentylenetetrazol. They found that almost 50 genes were turned on in the hippocampus of the resistant strain versus only a dozen in the sensitive strain.
“The next step is to determine which of these genes are most important for preventing cell death and to figure out how they do it,” said Barlow. “We hope that knowledge will lead to new therapies for treating human epileptics recovering from seizure trauma.”
Salk co-authors include Daniel G. Pankratz and Todd A. Carter. Collaborators include Rie Yasuda and Mark Mayford at the University of California, San Diego; and Jo A. Del Rio, Lisa Wodicka and David J. Lockhart at the Novartis Research Foundation in San Diego. The study, titled “Regional and strain-apecific gene expression mapping in the adult mouse brain,” was supported by the Frederick B. Rentschler Developmental Chair and the Esther A. and Joseph Klingenstein Fund.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.