Apr 17, 2009

Rett gene in amygdala linked to fear and learning

Deleting the gene associated with Rett syndrome from the amygdala region of mouse brains triggers anxiety and problems with learning and memory, according to research published today in the Journal of Neuroscience 1.

Researchers at the University of Texas Southwestern Medical Center at Dallas selectively deleted the MeCP2 gene, mutations in which cause Rett syndrome, from the amygdala — a clustering of cells in the brain that regulates the processing of emotions — of 3- to 5-month-old mice.

These mice, which express roughly 50 percent of normal MeCP2 levels in the amygdala, freeze when placed in a maze task routinely used to assess anxiety, the researchers found. The mice also have trouble remembering to anticipate a brief shock after an auditory tone — a task that control mice learn and remember after two tries — suggesting that MeCP2 regulates fear-dependent learning and memory.

Rett syndrome is a rare neurodevelopmental disorder that predominantly affects girls, and is characterized by distinctive hand movements, abnormal gait, seizures and mental retardation. Girls with the syndrome also often show features of autism, including anxiety, deficits in social skills and repetitive behavior.

Intriguingly, mice lacking MeCP2 in the amygdala show normal patterns of social interaction. “We were sort of surprised because it does suggest you can separate out anxiety from social interaction deficits,” says lead investigator Lisa Monteggia.

“For autism spectrum disorder, one of the most debilitating aspects is the social deficit,” Monteggia says. “So if we go back to other brain regions, could we recapitulate the social interaction deficits?”

A research team led by Huda Zoghbi in 1999 first linked mutations in the MeCP2 gene to Rett syndrome2, but the gene’s exact role is still unknown. Last year, the same group reported that the gene is a master regulator, controlling the activation and repression of thousands of other genes3.

Because MeCP2 is found throughout the body, it has been difficult to tease apart its contribution to the collection of symptoms seen in Rett syndrome. For example, mice that don’t have any MeCP2 are normal until 5 weeks of age, when they begin to develop Rett-like symptoms, and then die between 6 and 12 weeks of age4.

“When this protein is missing everywhere in the brain, the animals are so sick that you may miss hidden phenotypes,” Zoghbi says. “By looking at the gene just in specific areas, you might be able to learn the symptoms emanating from those specific brain regions.”

Regional deletions:
In 2001, Rudolf Jaenisch and colleagues created mice that lack the gene in the forebrain, a large region of the brain that includes the amygdala and performs a gamut of functions from sensory processing to memory, beginning at postnatal day 14, when neuronal connections are actively forming.

Monteggia’s group showed in 2006 that these mice have a broad array of Rett-like symptoms, including anxiety, learning and memory problems, deficits in motor coordination and social deficits5. The researchers then decided to focus specifically on the amygdala because anxiety, learning and memory tasks are regulated by the region.

Because some of Rett’s symptoms, including difficulty breathing and sleeping and elevated response to stress, implicate the hypothalamus, Zoghbi and her colleagues in September 2008 selectively deleted MeCP2 from the mouse hypothalamus and found that the mice are more aggressive and tend to eat more than do control littermates6.

In the new study, Monteggia and her colleagues also exposed normal mice to a histone deacetylase inhibitor — a chemical that enhances gene expression — and found that these normal mice and the MeCP2-deficient mice show similar behavioral deficits.

“To us, it suggested that these behavioral processes that we think MeCP2 is involved in were mediated through transcriptional repression,” Monteggia says.

Deletions from specific brain regions allow researchers to dissociate different brain functions that might involve different brain regions, says Mriganka Sur, chief of brain and cognitive sciences at the Massachusetts Institute of Technology. Still, to treat Rett syndrome, it will be important to intervene broadly in the brain, he notes.

Sur and his colleagues have found that treating mice that lack MeCP2 throughout the brain with insulin-like growth factor 1, a chemical that improves cell survival and maturation, improves the lifespan and locomotor activity7. The growth factor also strengthens connections between neurons, which is likely to be relevant to MeCP2’s role in regions like the amygdala.

“To my mind [the new study] argues that the MeCP2 gene is really involved in the kind of function that we postulated,” says Sur, “that MeCP2 is involved in synaptic maturation and regulating plasticity.”

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