Fragile-X Syndrome (FXS): Spaced training improves long term memory

Prominent characteristics of the syndrome include an elongated face, large or protruding ears, and low muscle tone. 

Credit: Wikipedia

Research on mice with Fragile X syndrome (FXS) suggests that multiple, spaced training sessions can enhance learning and long term memory when longer, continuous sessions do not.

Christine Gall and colleagues at the University of California Irvine tested mice with FXS on their ability to remember objects and locations and found that multiple training sessions, with 60-minutes breaks, allowed them to perform as well as healthy mice.

The research appears in the Proceedings of the National Academy of Sciences.

FXS is the most common cause of inherited intellectual disability. Previous studies have shown that mice with this condition have a problem with synaptic signaling in the hippocampus, which affects their ability to create long term memories.

Christine Gall

Gall's team wanted to see if they could create a training regime that would help overcome synaptic signaling problems and enable mice with FXS to learn normally.

They knew that individuals tend to learn better when trained in short, spaced trials rather than a single, long training episode, so they tested whether spaced training would help FXS mice.

The researchers tested the mice on object location memory (OLM) and novel object recognition (NOR).

To test OLM, they placed a mouse in a chamber that also contained two identical objects.

They gave the mouse time to examine the objects and remember their locations, and then removed the mouse. When the mouse was gone, the researchers moved one of the objects.

They then returned the mouse to the chamber. If the mouse spent more time exploring the new location than the old location, it was a sign that it had remembered the original location.

NOM testing involved replacing one of the identical objects with a different object, without changing its location.

Mice that spent more time examining the new object showed that they had remembered the original object.

After undergoing five minutes of continuous training and being removed from the chamber for 24 hours, wild mice recognized that one of the objects had moved or been replaced, but FXS mice did not.

However, when the researchers divided the training into three 100-second trials, with 60-minute intervals between them, the FXS mice performed about as well as the wild mice.

Gall's team examined hippocampal tissue from the mice and found that control FXS mice had problems with the activation of ERK1/2, a kinase needed for memory encoding.

Spaced training corrected this problem and restored proper signaling between synapses.

More information: Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice, PNAS, Ronald R. Seese, DOI: 10.1073/pnas.1413335111

Rett syndrome: Autism Spectrum Disorder Mice improve with synthetic oil

When young mice with the rodent equivalent of a rare autism spectrum disorder (ASD), called Rett syndrome, were fed a diet supplemented with the synthetic oil triheptanoin, they lived longer than mice on regular diets.

Importantly, their physical and behavioral symptoms were also less severe after being on the diet, according to results of new research from The Johns Hopkins University.

Researchers involved in the study think that triheptanoin improved the functioning of mitochondria, energy factories common to all cells.

Since mitochondrial defects are seen in other ASDs, the researchers say, the experimental results offer hope that the oil could help not just people with Rett syndrome, but also patients with other, more common ASDs.

A description of the research will be published on Oct. 9 in the journal PLOS ONE.

ASDs affect an estimated one in 68 children under 8 years of age in the United States. Rett syndrome is a rare ASD caused by mutations in the MECP2 gene, which codes for methyl-CpG-binding-protein 2 (MeCP2).

Rett syndrome includes autism-like signs, such as difficulty communicating, socializing and relating to others.

Other hallmarks are seizures, decreased muscle tone, repetitive involuntary movements, and gastrointestinal and breathing problems.

These other signs are also seen in some patients with other ASDs, suggesting underlying similarities in their causes.

While the causes of most ASDs are unknown and thought to be complex, Rett syndrome is unique, and could be a source of insight for the others, because it is caused by an error in a single gene.

The research team used mice lacking the MeCP2 protein, which left them with severe Rett syndrome.

In examining those mice, what stood out, according to Gabriele Ronnett, M.D., Ph.D., who led the research project at the Johns Hopkins University School of Medicine, was that they weighed the same as healthy mice but had large fat deposits accompanied by lower amounts of nonfat tissue, such as muscle.

This suggested that calories were not being used to support normal tissue function but instead were being stored as fat.

This possibility led Ronnett and her research team to consider the role of mitochondria, which transform the building blocks of nutrients into a high-energy molecule, ATP.

This molecule drives processes such as the building of muscle and the growth of nerve cells.

Mitochondria use a series of biochemical reactions, collectively called the TCA cycle, to make this transformation possible.

According to Susan Aja, Ph.D., a research associate and lead member of the research team, "If the components of the TCA cycle are low, nutrient building blocks are not processed well to create ATP. They are instead stored as fat."

Ronnett suspected, she says, that some of Rett syndrome's neurological symptoms could stem from metabolic deficiencies caused by faulty mitochondria and reduced energy for brain cells.

"Rett syndrome becomes apparent in humans 6 to 18 months old, when the energy needs of the brain are particularly high, because a lot of new neural connections are being made," says Ronnett.

"If the mitochondria are already defective, stressed or damaged, the increased demand would be too much for them."

Previous small clinical trials in people with a different metabolic disorder suggested that dietary intervention with triheptanoin could help.

Triheptanoin is odourless, tasteless and a little thinner than olive oil. It is easily processed to produce one of the components of the TCA cycle.

When Rett syndrome mice were weaned at 4 weeks of age, they were fed a diet in which 30 percent of their calories came from triheptanoin, mixed in with their normal pelleted food.

Though far from a cure, the results of the triheptanoin treatment were impressive, the researchers say.

Treated mice had healthier mitochondria, improved motor function, increased social interest in other mice and lived four weeks, or 30 percent, longer than mice who did not receive the oil. The team also found that the diet normalized their body fat, glucose and fat metabolism.

"You can think of the mitochondria of the Rett syndrome model mice as damaged buckets with holes in them that allow TCA cycle components to leak out," says Aja.

"We haven't figured out how to plug the holes, but we can keep the buckets full by providing triheptanoin to replenish the TCA cycle."

"It is still too early to assume that this oil will work in humans with ASDs, but these results give us hope," says Ronnett.

"It's exciting to think that we might be able to improve many ASDs without having to identify each and every contributing gene."

According to Aja, additional mouse studies are needed to learn if female mice respond to the treatment, to perform a wider range of physiology and behavior tests, and, importantly, to assess the effects of triheptanoin treatment on the brain, which is considered the main driver of many Rett symptoms.

The team would also like to provide triheptanoin at earlier ages, perhaps via the mothers' milk, to mimic developmental ages at which most children are diagnosed with Rett syndrome.

Triheptanoin is currently made for research purposes only and is not available as a medicine or dietary supplement for humans.

More information: PLOS ONE: dx.plos.org/10.1371/journal.pone.0109527

Diabetes Reversed In Mice Thanks To Stem Cell Transplant

Canadian scientists were able to reverse diabetes in mice with a human stem cell transplant, igniting hopes for a cure for the widespread disease, caused by the failure of the pancreas to produce enough insulin to stabilize blood sugar levels in humans.

A paper outlining the work, led by Timothy Kieffer of the University of British Columbia and conducted in partnership with New Jersey-based company BetaLogics, appeared in the journal Diabetes on Tuesday.

Diabetic mice were weaned off of insulin after receiving the pancreatic stem cell transplant, which restarted the cycle in which insulin production rises or falls based on blood sugar levels.  Three to four months later, the mice could maintain healthy blood sugar levels even after being fed a lot of sugar.

"We are very excited by these findings, but additional research is needed before this approach can be tested clinically in humans," Kieffer said in a statement on Tuesday.

The researchers cautioned that their study used mice that had a suppressed immune system, the better to prevent rejection of the transplanted cells.

"We now need to identify a suitable way of protecting the cells from immune attack so that the transplant can ultimately be performed in the absence of any immunosuppression," Kieffer said.

In 2009, a different team of researchers led by scientists from the University of Sao Paulo in Brazil and Northwestern University reported in the Journal of the American Medical Association that they were able to successfully reverse type 1 diabetes by injecting 8 patients with some of their own stem cells.

Some studies have shown that this kind of stem cell transplantation is only a temporary fix - after anywhere between six months to three years, the insulin-producing cells are again attacked by the patient's immune system.

SOURCE: Rezania et al. "Maturation of Human Embryonic Stem Cell-Derived Pancreatic Progenitors into Functional Islets Capable of Treating Pre-existing Diabetes in Mice." Diabetes 27 June 2012.