Scientists are developing new ways to selectively boost gene expression in the brain, in the hope of treating psychiatric and neurological disease. A growing pool of evidence shows that compounds that target this mechanism can improve learning and memory in rodents. But existing drugs, which were not developed for this purpose, are relatively weak and unselective, and their long-term safety is not yet clear.

Over the past few years, neuroscientists have begun to recognize the importance of epigenetics--molecular processes that change the expression of genes without altering DNA--in the brain, and in memory in particular. One of the key regulators of epigenetics is a group of enzymes known as histone deacetylases (HDACs), which trigger DNA to wind more tightly around neighboring proteins, ultimately dampening gene expression. Recent studies have shown that existing drugs that inhibit these enzymes can enhance learning in both normal mice and those that are cognitively impaired.

"I think the implication for human disease is really exciting," says Li-Huei Tsai, a neuroscientist at MIT. Last year, Tsai's group showed that giving brain-damaged mice an HDAC inhibitor allowed them to recall lost memories.

EnVivo Pharmaceuticals, a drug company based in Watertown, MA, is developing HDAC inhibitors that are more potent than existing ones and can easily enter the brain. (Valproic acid, for example, a drug used to treat epilepsy and bipolar disorder and currently being tested for cancer, is a relatively weak inhibitor.) According to results presented at a neuroscience conference last month, the company's lead HDAC inhibitor can enhance both short- and long-term memory in mice. The company hopes to test the drug in the next year, says Michael Ahlijanian, vice president of research at EnVivo.

While scientists don't yet know exactly how epigenetic regulation affects memory, the theory is that certain triggers, such as exercise, visual stimulation, or drugs, unwind DNA, allowing expression of genes involved in neural plasticity. That increase in gene expression might trigger development of new neural connections and, in turn, strengthen the neural circuits that underlie memory formation. "Maybe our brains are using these epigenetic mechanisms to allow us to learn and remember things, or to provide sufficient plasticity to allow us to learn and adapt," says John Satterlee, program director of epigenetics at the National Institute on Drug Abuse, in Bethesda, MD.

"We have solid evidence that HDAC inhibitors massively promote growth of dendrites and increase synaptogenesis [the creation of connections between neurons]," says Tsai. The process may boost memory or allow mice to regain access to lost memories by rewiring or repairing damaged neural circuits. "We believe the memory trace is still there, but the animal cannot retrieve it due to damage to neural circuits," she adds.

The safety of more potent HDAC inhibitors, especially those that target the brain, is not yet clear. A paper published today in Neuron highlights potential problems. Tsai and her colleagues found that inhibiting a specific HDAC enzyme increased cell damage and death in rodents with symptoms of Alzheimer's disease, while increasing levels of the enzyme-protected neurons.

The findings suggest that scientists will need to develop compounds that act selectively on the different HDAC enzymes, perhaps inhibiting some and activating others. At this point, little is known about the specific functions of the nearly 20 different enzymes. But Tsai says that her group has identified one enzyme that appears to be specifically involved in memory. The researchers are also developing more selective compounds. "We hope to have something in the near future that we feel comfortable evaluating in people," says Tsai.