To make a memory that lasts, neurons need to regulate the activity of genes. One way to do this is with proteins that latch onto DNA and inhibit or enhance the expression of specific genes. But that's not the only trick neurons have at their disposal. A new study finds that neurons can also regulate gene expression by chemically modifying the genes themselves.
During development, the brain uses "epigenetic" mechanisms to make long-term changes in gene expression. One example involves enzymes that work on histones--proteins that act like spools to keep DNA tightly packaged--in a way that makes certain genes more or less accessible. Another example is DNA methylation, in which enzymes add a chemical modification called a methyl group that silences a gene (ScienceNOW, 12 April 2006). Until recently, however, there was little evidence that such epigenetic changes played a role in the fully developed nervous system.
In the new study, neurobiologists Courtney Miller and David Sweatt of the University of Alabama, Birmingham, injected rats with a drug that inhibited DNA methylation immediately after the rats had received three mild electrical shocks. Normally, rats remember such an unpleasant experience and freeze up when returned to the same enclosure the following day. Not so for the injected rats: They showed about one-fourth the freezing behavior of uninjected rats, indicating a much weaker memory, Miller and Sweatt report online today in Neuron.
To investigate how DNA methylation might affect memory, the researchers then looked for specific memory-related genes whose activity was altered by DNA methylation after the shock-box experience. Miller and Sweatt found increased methylation of a gene called PP1, whose activity has been previously shown to suppress learning and memory. They also found reduced PP1 expression, consistent with the idea that methylation silences genes. At the same time, they observed decreased methylation and increased expression of a memory-promoting gene called reelin. The methylation changes in both genes favor learning and memory, Sweatt notes. Along with recent studies on histone modifications in the adult nervous system, the new work adds to growing evidence that epigenetic mechanisms may contribute to learning and memory, Sweatt says.
"It's very provocative," says Lisa Monteggia, a neurobiologist at the University of Texas Southwestern Medical Center in Dallas. "Classically, DNA methylation has been viewed as one of the most permanent ways to modify DNA and alter gene expression." But in the new study, methylation levels of PP1 and reelin changed within an hour of learning and returned to normal 24 hours later, Monteggia points out. That suggests that DNA methylation can be a far more dynamic process than many researchers assumed, she says.
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