The problems people with autism have with memory formation, higher-level thinking and social interactions may be partially attributable to the activity of receptors inside brain cells, researchers at Washington University School of Medicine in St. Louis have learned.

Scientists were already aware that the type of receptor in question was a potential contributor to these problems – when located on the surfaces of brain cells. Until now, though, the role of the same type of receptor located inside the cell had gone unrecognized. Such receptors inside cells significantly outnumber the same type of receptors on the surface of cells.

The receptor under study, known as the mGlu5 receptor, becomes activated when it binds to the neurotransmitter glutamate, which is associated with learning and memory. This leads to chain reactions that convert the glutamate's signal into messages traveling inside the cell.

In the new study, scientists working with cells in a dish linked mGlu5 receptors inside cells to processes that turn down the volume at which brain cells talk to each other. These volume changes, essential for learning and memory, may become exaggerated in people with autism.

Pharmaceutical companies have developed therapeutic compounds to decrease signaling associated with the mGlu5 receptor, moderating its effects on brain cells' volume knobs. But the compounds were designed to target mGlu5 surface receptors. In light of the new findings, the scientists question if those drugs will reach the receptors inside cells.

"Our results suggest that to have the greatest therapeutic benefit, we may need to make sure we're blocking all of this type of receptor, both inside and on the surface of the cell," said senior investigator Karen O'Malley, PhD, professor of neurobiology.

The findings, published March 25 in The Journal of Neuroscience, also add a significant new dimension to basic brain cell function. Scientists have long assumed that brain cell receptors are only active on the surface of cells. The new study shows that receptors can be active inside cells, and their effects can be considerably different from the same receptors located on the cell surface.

"The traditional wisdom was that receptors inside the cell were either waiting to go to work on the surface or had just finished working there," said O'Malley. "But when we compared how much of the mGlu5 receptor was on the surface of cells to how much was inside it, we were seeing so much more receptor inside the cell – at least 50 percent, and in some cases as much as 90 percent – that we wondered if the interior receptors had separate functions."

In earlier studies, O'Malley and her collaborators showed that mGlu5 receptors on the cell surface sent completely different messages than the same receptors inside the cell.

The scientists knew that most autism studies were conducted with compounds that blocked mGlu5 receptors but could not get into the cell. To determine whether blocking inside receptors would have different effects, O'Malley collaborated with Yukitoshi Izumi, MD, PhD, research professor of psychiatry, and Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, who study cell-based models of learning and memory.

When the scientists examined these model systems using compounds that allowed them to activate only mGlu5 receptors within cells, they found that these receptors played a bigger role in turning down the volume of brain cell communications than did the cell surface receptors.

In the last few years, scientists have found that 20 or more types of brain cell receptors located on cell surfaces also are present at high levels inside cells, O'Malley noted.

"This should be a factor we consider when we design drugs to target brain cell receptors," she said. "Do we want to reach cell surface receptors, receptors inside the cell or both?"

More information: Purgert CA, Izumi Y, Jong Y-J I, Kumar V, Zorumski CF, O'Malley KL. Intracellular mGluR5 can mediate synaptic plasticity in the hippocampus. TheJournal of Neuroscience, March 25, 2014.

(Medical Xpress)—A new study co-authored by a Simon Fraser University researcher finds the children of pregnant women exposed to high levels of a flame retardant and a banned pesticide are more likely to exhibit autistic-like behaviours.

The flame retardant is PBDE-28. Chlordane is the banned pesticide. It contains the chemical trans-nonachlor, which this study links to autistic-like behaviours.

Previous studies have linked changes in children's brain development to their mothers' exposure to hormone-disrupting environmental chemicals. But this study is one of only a few to look specifically at whether chemical exposure contributes to autistic behaviours.

Bruce Lanphear, an SFU health scientist involved in this study published online in the journal Environmental Health Perspectives, says: "This type of study is critical to screening the myriad chemicals that pregnant women and children are exposed to, and to identifying the ones that elevate a child's risk of developing autism."

April 2 is World Autism Day. Autism now affects one in 88 children and one in 54 boys, worldwide.

Scientists suspect that hormones may play a role in autism because boys are four times more likely than girls to be diagnosed with the disorder, and sex hormones are known to modify brain development.

In this latest study, researchers tested urine and blood samples from 175 pregnant women in the Cincinnati, Ohio area. On average, the pregnant women had 44 suspected hormone-disrupting chemicals in their blood or urine.

When their children turned four or five, their mothers were asked to rate their behaviours on a scale of social responsiveness, such as how frequently they make eye contact when spoken to or how well they play with others. Higher scores mean more autistic behaviours.

Children whose mothers had the highest levels of PBDE-28 scored an average of 2.5 points higher on the scale than children whose mothers had the lowest exposures. Children whose mothers had the highest levels of trans-nonachlor scored an average of 4.1 points higher.

The increase in autism-like behaviours linked to the two chemicals was subtle, and the study doesn't prove that they are tied to the autistic behaviours.

Most children scored between 30 and 90 on the scale, with scores higher than 60 indicating significant deficiencies in social behaviour. Children, on average, scored 51, while 22 kids, about 12 per cent, scored higher than 60.

The researchers did not account for factors such as genetics or other contaminants, such as lead, that harm brain development. Nor did they examine exposures or factors after birth.

But Lanphear and his collaborators in this study acknowledge that more research is necessary to investigate the link between autism and exposure to a now banned pesticide.

More information: Paper: ehp.niehs.nih.gov/1307261/