Neuroscience long held that when a fetus is fully developed, a process called DNA methylation stops. (DNA methylation involves adding a bulky methyl group to a gene's DNA backbone, which obstructs the process of translating it into a protein.) The thinking was that since neurons or nerve cells are no longer replicating, there is no need for genes to be turned off (or on via demethylation), which happens as new cells morph into different roles in the nervous system.
New evidence has been mounting to the contrary, however, since 1987 when an enzyme that carries out methylation was found in the neurons of adults. A study in this week's Neuron provides key evidence that DNA methylation—also known to occur as cancerous cells divide, when tumor suppressor genes are silenced—occurs in adult brains and can be triggered by environmental cues. Study co-author David Sweatt, a neurobiologist at the University of Alabama at Birmingham, says the finding could provide new targets for treating mental illnesses such as schizophrenia and the autism-spectrum disorder Rett, conditions in which improper methylation switches off certain genes during development.
Recent research has shown that structural changes take place in chromatin (the complex that houses DNA in cells) while memories are being created. Methylation is among the so-called epigenetic processes—those not specifically designed to affect the genes—that can alter chromatin. So, Sweatt and study co-author Courtney Miller, a postdoctoral researcher, set about to determine if methylation plays a role in memory formation, homing in on the hippocampus, two curved regions in the mid-brain implicated in episodic memory.
They did this by training mice to fear a certain environment by sending mild shocks to their feet in a closed box. They removed the mice for 24 hours, but when placed back in the box, the mice adopted a frightened, frozen posture, indicating that they remembered their shocking experience there. The researchers removed hippocampal slices as they carried out the study to see whether any methylation or demethylation had taken place. "We had to take an educated guess as to what things might be changing in regards to their methylation state," Sweatt says. The team focused on two specific genes: protein phosphatase 1 (PP1), a known memory suppressor, and reelin, a memory-promoting gene.
Sure enough, within an hour of the exercise, reelin had been demethylated or switched on and PP1 had been shut down. The team repeated the experiment after the mice were given drugs to inhibit methylation. The results: the animals exhibited no fear when placed in the shock box again, indicating that the memory had not been stored.
Sweatt believes that his findings in the hippocampus apply to other regions involved in memory processing, including the cortex, the brain's outermost layer, and the amygdala, two almond-shaped structures in the midbrain. "I would speculate that this regulation of DNA methylation might well be a generic molecular device that's involved in all memory formation," he says. "Neurons everywhere may use this fundamental mechanism."
Moshe Szyf, a neuropharmacologist at McGill University in Montreal, enthusiastically embraced the team's findings. "Although the dogma in the field has long been that DNA methylation is fixed after birth, especially in nondividing cells such as neurons, I strongly believed that this notion was wrong and that DNA methylation, like any other known biological signal, was reversible," he says. "I strongly believe that DNA methylation/demethylation plays a critical role in learning and memory."
Sweatt agrees the findings could have implications for cognitive disorders like Rett syndrome and schizophrenia. In schizophrenia, for example, it is known that too little reelin is released because of faulty methylation. Because DNA methylation is "in play" in the adult brain, Sweat says, these disorders may be more susceptible to intervention and "may not be as locked in as people may have thought."
Dennis Grayson, a molecular neurobiologist at the University of Illinois at Chicago, says this finding could shift schizophrenia treatment to the "pharmacology of chromatin biology rather than the pharmacology of receptors." Traditional antipsychotic drugs, which have been used for 40 years, are known to alleviate symptoms of the disorder in some patients by blocking receptors of dopamine, a neurotransmitter that is central to the brain's reward system as well as cognitive processing like attention and problem-solving. "We may need to focus on drugs that modify chromatin in a way that decreases methylation," Grayson says, to "turn on genes that are missing in the schizophrenia."
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