Autistic brain 'overloaded with connections'

"Scientists discover people with autism have too many brain 'connections'," the Mail Online reports. US research suggests that people with an autistic spectrum disorder have an excessive amount of neural connections inside their brain.

The headline is based on the results of a study that found that at post-mortem, brains of people with autism spectrum disorder (ASD) have more nerve cell structures called “dendritic spines” – which receive signals from other nerve cells – than the brains of people without ASD.

Brain development after birth involves both the formation of new connections and the elimination or "pruning" of other connections. The researchers concluded that people with ASD have a developmental defect in the pruning/elimination of dendritic spines.

Further examination of the brains of people with ASD found that more of the signalling protein mTOR was found to be in its activated state than in brains of people without ASD.

A process called autophagy, where older structures and proteins within cells are removed and broken down, was also impaired.

The researchers performed further experiments to show the mTOR signalling inhibits autophagy, and without autophagy pruning of dendritic spines does not occur.

Mice genetically engineered to have increased levels of activated mTOR signalling were found to display autistic-like symptoms. All of these could be reversed with treatment with an inhibitor of mTOR called rapamycin.

Rapamycin is a type of antibiotic, and is currently used in medicine as an immunosuppressant to prevent organ rejection after kidney transplant. However, it has been associated with a range of adverse effects so would be unsuitable for most people with ASD.

It is too soon to say whether this research could lead to any treatment for ASD, and even if it does it is likely to be a long way off.

Where did the story come from?

The study was carried out by researchers from Columbia Medical School, the Icahn School of Medicine at Mount Sinai and the University of Rochester. It was funded by the Simons Foundation.

The study was published in the peer-reviewed journal Neuron.

The results of the study were extremely well-reported by the Mail Online.

What kind of research was this?

This was a laboratory and animal study that aimed to determine whether a process called autophagy (a process of removing and degrading cell structures and proteins) is involved in the remodelling of synapses (nerve connections). And whether this involves signalling through a protein called mTOR.

They also wanted to see whether this process was defective in autism spectrum disorder (ASD).

Laboratory and animal-based research is ideal for answering these sorts of questions. However, it means that any application to human health is probably a long way off.

What did the research involve?

The researchers initially examined at post-mortem the brains of people with ASD and people without ASD. They were particularly interested in nerve cell structures called “dendritic spines”, which receive signals from other nerve cells.

The researchers performed experiments with mice genetically engineered to have symptoms of ASD. In these mice models the signalling protein mTOR is dysregulated.

The researchers also performed further experiments to study the effects of mTOR dysregulation and blockage of autophagy.

What were the basic results?

From examining the brains of people with ASD and comparing them with the brains of people without ASD the researchers found that the density of dendritic spines was significantly higher in ASD.

Brain development after birth involves both the formation of new nerve connections and the pruning/elimination of others. The formation of new nerve connections exceeds pruning during childhood, but then synapses are eliminated during adolescence as synapses are selected and matured.

When the researchers compared the brains of children (aged between two and nine) and adolescents (aged between 13 and 20) they found that spine density was slightly higher in children with ASD compared to controls, but was markedly higher in adolescents with ASD compared to controls.

From childhood through adolescence, dendritic spines decreased by approximately 45% in control subjects, but by only approximately 16% in those with ASD. The researchers concluded that people with ASD have a developmental defect in spine pruning/elimination.

The researchers found there were higher levels of the activated version of the signalling protein mTOR in adolescent ASD brains than brains without ASD. They also found ASD brains were not performing as much autophagy as brains without ASD.

The researchers then performed experiments using mice models of ASD that had dysregulated mTOR. They found the mice had spine pruning defects. These pruning defects could be improved by treating the mice with a chemical called rapamycin which inhibits mTOR. The nerve cells of the mice models of ASD also performed less autophagy, and this was also corrected by treating the mice with rapamycin. Rapamycin also improved social behaviour of the mice on behavioural tests.

How did the researchers interpret the results?

The researchers conclude that their “findings suggest mTOR-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behaviour deficits in ASD models with hyperactivated mTOR".

Conclusion

This study has found that brains of people with ASD have more nerve cell structures called “dendritic spines”, which receive signals from other nerve cells, than the brains of people without ASD. More of the signalling protein mTOR was found to be in its activated state and a process called autophagy, which the cell uses to remove and degrade cell structures and proteins, was impaired in brains from people with ASD.

Genetically engineered mice with hyperactivated mTOR display autistic-like symptoms, have more dendritic spine pruning defects and impaired autophagy. All of these could be reversed with treatment with an inhibitor of mTOR called rapamycin.

Rapamycin is a type of antibiotic, and is currently used in medicine as an immunosuppressant to prevent organ rejection after kidney transplantation.

However, it has been associated with a range of adverse effects. As the Mail points out, this research is in its very early stages. It mainly helps our understanding of the brain changes that may be involved in this condition.

It is too soon to say whether it could lead to any treatment for autism spectrum disorders, and even if it does it is likely to be a long way off.