August 10, 2012

Scientists affiliated with the UC Davis MIND Institute have discovered how a defective gene causes brain changes that lead to the atypical social behavior characteristic of autism. The research offers a potential target for drugs to treat the condition.

Earlier research already has shown that the gene is defective in children with autism, but its effect on neurons in the brain was not known. The new studies in mice show that abnormal action of just this one gene disrupted energy use in neurons. The harmful changes were coupled with antisocial and prolonged repetitive behavior — traits found in autism.

The research is published online today in the scientific journal PLoS ONE.

"A number of genes and environmental factors have been shown to be involved in autism, but this study points to a mechanism — how one gene defect may trigger this type of neurological behavior," said study senior author Cecilia Giulivi, professor of molecular biosciences in the UC Davis School of Veterinary Medicine and a researcher affiliated with the UC Davis MIND Institute. 

"Once you understand the mechanism, that opens the way for developing drugs to treat the condition," she said.

The defective gene appears to disrupt neurons’ use of energy, Giulivi said, the critical process that relies on the cell’s molecular energy factories called mitochondria. 

In the research, a gene called pten was tweaked in the mice so that neurons lacked the normal amount of pten’s protein. The scientists detected malfunctioning mitochondria in the mice as early as 4 to 6 weeks after birth.

By 20 to 29 weeks, DNA damage in the mitochondria and disruption of their function had increased dramatically. At this time the mice began to avoid contact with their litter mates and engage in repetitive grooming behavior. Mice without the single gene change exhibited neither the mitochondria malfunctions nor the behavioral problems.

The antisocial behavior was most pronounced in the mice at an age comparable in humans to the early teenage years, when schizophrenia and other behavioral disorders become most apparent, Giulivi said.
 
The research showed that, when defective, pten’s protein interacts with the protein of a second gene known as p53 to dampen energy production in neurons. This severe stress leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus — brain regions critical for social behavior and cognition.

Pten mutations previously have been linked to Alzheimer’s disease as well as a spectrum of autism disorders. The new research shows that when pten protein was insufficient, its interaction with p53 triggered deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism.

Source: UCDavis

ScienceDaily (Aug. 9, 2012) — Manipulating a group of hormone-producing cells in the brain can control blood sugar levels in the body — a discovery that has dramatic potential for research into weight-loss drugs and diabetes treatment.

Erik Johnson uses the fruit fly, Drosophila, to look at an enzyme called AMP-activated kinase and its role in signaling the hormone that elevates the level of sugar in the blood. (Credit: Image courtesy of Wake Forest University)

In a paper published in the October issue of Genetics and available online now, neurobiologists at Wake Forest University examine how fruit flies (Drosophila) react when confronted with a decreased diet.

Reduced diet or starvation normally leads to hyperactivity in fruit flies — a hungry fly buzzes around feverishly, looking for more food. That happens because an enzyme called AMP-activated kinase stimulates the secretion of the adipokinetic hormone, which is the functional equivalent of glucagon. This hormone acts opposite of insulin, as it tells the body to release the sugar, or food, needed to fuel that hyperactivity. The body uses up its energy stores until it finds food.

But when Wake Forest’s Erik Johnson, an associate professor of biology, and his research team turned off AMP-activated kinase, the cells decreased sugar release and the hyperactive response stopped almost completely — even in the face of starvation.

"Since fruit flies and humans share 30 percent of the same genes and our brains are essentially wired the same way, it suggests that this discovery could inform metabolic research in general and diabetes research specifically," said Johnson, the study’s principal investigator. "The basic biophysical, biochemical makeup is the same. The difference in complexity is in the number of cells. Why flies are so simple is that they have approximately 100,000 neurons versus the approximately 11 billion in humans."

Medical advances as a result of this research might include:

• Diabetes research: Adipokinetic hormone is the insect equivalent to the hormone glucagon in the human pancreas. Glucagon raises blood sugar levels; insulin reduces them. However, it is difficult to study glucagon systems because the pancreatic cells are hard to pull apart. Studying how this similar system works in the fruit fly could pave the way to a drug that targets the cells that cause glucagon to tell the body to release sugar into the blood — thus reducing the need for insulin shots in diabetics.

• Weight-loss drugs: An “exercise drug” would turn on all AMP-activated kinase in the body and trick the body into thinking it was exercising. “Exercise stimulates AMP-activated kinase, so manipulation of this molecule may lead to getting the benefits of exercise without exercising,” Johnson said. In previous research published in the online journal PLoS ONE, Johnson and his colleagues found that, when you turn off AMP-activated kinase, you get fruit flies that “eat a lot more than normal flies, move around a lot less, and end up fatter.”

Source: Science Daily

THURSDAY, Aug. 9 (HealthDay News) — Researchers report that they have created a device able to short-circuit epileptic seizures in rats.

Similar in design to an implantable defibrillator, the device is placed in the brain and reacts only when a seizure starts to occur, essentially aborting the seizure’s electrical activity.

The self-adjusting device electrically stimulates the brain at the beginning of a short but frequent type of seizure in rats, and then automatically shuts itself off. The research was published in the Aug. 10 issue of the journal Science.

"It works like a ping-pong game," explained study author Dr. Gyorgy Buzsaki, a professor of neural science at New York University. "Every time a ball is coming your way, you apply an interfering pattern to whack it away."

Epilepsy is a brain disorder in which a person has repeated seizures over time. It affects nearly 3 million Americans, according to the Epilepsy Foundation, making it the third most common neurological disorder in the United States, after Alzheimer’s and stroke.

People with epilepsy can suffer from two different kinds of seizures: petit mal seizures, which last for just a few seconds but can occur frequently, and grand mal seizures, which are rare but involve violent muscle contractions and a loss of consciousness.

Seizures are episodes of disturbed brain activity that cause changes in attention or behavior. Brain cells keep firing instead of acting in an organized way. The malfunctioning electrical system of the brain causes surges of energy that can cause unconsciousness and muscle contractions.

The researchers tested the new device against petit mal seizures in rats because this type of seizure occurs hundreds of times a day. The sheer volume of the seizures allowed the scientists to effectively test the system they designed. People with petit mal seizures are typically treated effectively with drugs, so the device would not be used to treat that type of seizure.

In what Buzsaki describes as a simple, closed-loop system, the firing of brain neurons creates a spike in neurological activity that is followed by a wave and detected by the device, which fires back only when necessary. The system, called transcranial electrical stimulation, leaves other aspects of brain function unaffected. “The system doesn’t prevent seizures, it just treats them right away,” said Buzsaki. The stimulation reduced the length of a seizure by about 60 percent.

In humans, two plates about the size of a pocket watch could be placed in the skull in a position designed to target the affected area of the brain. The electrodes would be powered by ultralight electrical circuits implanted in the skull, Buzsaki explained.

The goal is to apply the system that worked in rats to people with complex partial seizures — epileptic seizures that affect both sides of the brain and cause a loss of consciousness, Buzsaki said. Although the device worked in rats, the results may not translate to humans.

This type of seizure also can occur with head injuries, brain infection and stroke. The cause is typically unknown.

In 20 percent to 40 percent of people who have complex partial seizures, drugs are ineffective and there are no remedies, Buzsaki said. “It’s not clear what kind of stimulation to deliver and where exactly in the brain the stimulation should go,” he explained.

Dr. Orrin Devinsky, director of the epilepsy program at New York University, said the research has enormous potential for treating epilepsy and other neurological problems. “What’s unique about this technique is that it’s a sophisticated way to identify the rhythmicity of the seizure itself and interrupt the cycle with precision,” he said. “Existing [deep brain stimulation] devices don’t finesse the timing this way.”

Devinsky, who was not associated with the study, said the research could potentially be applicable to people with tremors, Parkinson’s disease and even those with serious depression and other psychological disorders.

Source: HealthDay