Children with autism have extra synapses in brain

In a study of brains from children with autism, researchers found that autistic brains did not undergo normal pruning during childhood and adolescence. 

The images show representative neurons from autistic (left) and control (right) brains; the spines on the neurons indicate the location of synapses.

Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center

Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain "pruning" process during development, according to a study by neuroscientists at Columbia University Medical Center (CUMC).

Because synapses are the points where neurons connect and communicate with each other, the excessive synapses may have profound effects on how the brain functions.

The study was published in the August 21 online issue of the journal Neuron.

A drug that restores normal synaptic pruning can improve autistic-like behaviors in mice, the researchers found, even when the drug is given after the behaviours have appeared.

"This is an important finding that could lead to a novel and much-needed therapeutic strategy for autism," said Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chair of Psychiatry at CUMC and director of New York State Psychiatric Institute, who was not involved in the study.

Although the drug, rapamycin, has side effects that may preclude its use in people with autism, "the fact that we can see changes in behaviour suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug," said the study's senior investigator, David Sulzer, PhD, professor of neurobiology in the Departments of Psychiatry, Neurology, and Pharmacology at CUMC.

David Sulzer

During normal brain development, a burst of synapse formation occurs in infancy, particularly in the cortex, a region involved in autistic behaviours; pruning eliminates about half of these cortical synapses by late adolescence.

Synapses are known to be affected by many genes linked to autism, and some researchers have hypothesized that people with autism may have more synapses.

To test this hypothesis, co-author Guomei Tang, PhD, assistant professor of neurology at CUMC, examined brains from children with autism who had died from other causes.

Thirteen brains came from children ages two to 9, and thirteen brains came from children ages 13 to 20. Twenty-two brains from children without autism were also examined for comparison.

Dr. Tang measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from these cortical neurons; each spine connects with another neuron via a synapse.

By late childhood, she found, spine density had dropped by about half in the control brains, but by only 16 percent in the brains from autism patients.

"It's the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism," Dr. Sulzer said, "although lower numbers of synapses in some brain areas have been detected in brains from older patients and in mice with autistic-like behaviours."


Clues to what caused the pruning defect were also found in the patients' brains; the autistic children's brain cells were filled with old and damaged parts and were very deficient in a degradation pathway known as "autophagy."

Cells use autophagy (a term from the Greek for self-eating) to degrade their own components. Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR.

When mTOR is overactive, they found, brain cells lose much of their "self-eating" ability and without this ability, the brains of the mice were pruned poorly and contained excess synapses.

"While people usually think of learning as requiring formation of new synapses, "Dr. Sulzer says, "the removal of inappropriate synapses may be just as important."

The researchers could restore normal autophagy and synaptic pruning, and reverse autistic-like behaviors in the mice, by administering rapamycin, a drug that inhibits mTOR.

The drug was effective even when administered to the mice after they developed the behaviors, suggesting that such an approach may be used to treat patients even after the disorder has been diagnosed.

Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the same processes may occur in children with autism.

"What's remarkable about the findings," said Dr. Sulzer, "is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning.

This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River.

Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behaviour, may be a unifying feature of autism."

Alan Packer, PhD, senior scientist at the Simons Foundation, which funded the research, said the study is an important step forward in understanding what's happening in the brains of people with autism.

"The current view is that autism is heterogeneous, with potentially hundreds of genes that can contribute."

"That's a very wide spectrum, so the goal now is to understand how those hundreds of genes cluster together into a smaller number of pathways; that will give us better clues to potential treatments," he said.

"The mTOR pathway certainly looks like one of these pathways. It is possible that screening for mTOR and autophagic activity will provide a means to diagnose some features of autism, and normalizing these pathways might help to treat synaptic dysfunction and treat the disease."

Journal Reference: 
Guomei Tang, Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai Yamamoto, Zhenyu Yue, Ottavio Arancio, Bradley S. Peterson, Frances Champagne, Andrew J. Dwork, James Goldman, David Sulzer. "Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits." Neuron, 2014; DOI: 10.1016/j.neuron.2014.07.040

Fewer Synapses, More Efficient Learning: Molecular Glue Wires the Brain

Yale University researchers have found that a single molecule not only connects brain cells but also changes how we learn. The findings, reported in the December 9 issue of the journal Neuron, may help researchers discover ways to improve memory and could lead to new therapies to correct neurological disorders.

The junctions between brain cells over which nerve pulses pass -- called synapses -- are crucial for regulating learning and memory and how we think. Aberrations in the structure and function of synapses have been linked to mental retardation and autism, while synapses are lost in the aging brains of Alzheimer's patients.

However, the mechanisms that organize synapses in the living brain remain a puzzle. Yale scientists identified one critical piece of this puzzle, a molecule called SynCAM 1 that spans across synaptic junctions.

"We hypothesized that this molecule might promote new synapses in the developing brain, but were surprised that it also impacts the maintenance and function of these structures," said Thomas Biederer, associate professor of molecular biophysics and biochemistry and senior author of the study. "We can now define how this molecule supports the brain's ability to wire itself."

The Yale team focused on SynCAM 1, an adhesion molecule that helps to hold synaptic junctions together. They found that when the SynCAM 1 gene was activated in mice, more synaptic connections formed. Mice without the molecule produced fewer synapses.

When we learn, new synapses can form. However, the strength of synaptic connections also changes during learning, based on the amount of stimuli received -- a quality scientists termed "plasticity." Together with a group in Germany led by Valentin Stein, the team was surprised to find that SynCAM 1 controls an important form of synaptic plasticity.

Unexpectedly, Biederer and colleagues also found that mice with high amounts of SynCAM 1 are unable to learn while mice lacking SynCAM 1 -- and having fewer synapses -- learn better. Apparently an excess of the molecule can be damaging. This builds on recent theories suggesting that having too many connections isn't always better and that the balance of synaptic activity is crucial for proper learning and memory.

"Synapses are dynamic structures. It appears that SynCAM 1 ties synapses together; some of this molecule is needed to promote contact but too much glues down the synapse and inhibits its function. It may act a bit like a sculptor who helps give synapses their shape." Biederer also said that the molecule is almost identical in mice and man, and likely has the same roles in human brains.

Journal Reference:

1. Elissa M. Robbins, Alexander J. Krupp, Karen Perez De Arce, Ananda K. Ghosh, Adam I. Fogel, Antony Boucard, Thomas C. Südhof, Valentin Stein, Thomas Biederer. SynCAM 1 adhesion dynamically regulates synapse number and impacts plasticity and learning. Neuron, 2010; 68 (5): 894-906 DOI: 10.1016/j.neuron.2010.11.003

Research Claims Ritalin Improves Ability to Learn

Research Claims Ritalin Improves Ability to Learn

Ritalin (methylphenidate), a drug prescribed for millions of children who have attention deficit hyperactivity disorder (ADHD), appears to improve the ability to learn by enhancing the speed of learning. Currently, Ritalin is prescribed to help inhibit impulsive behaviour, which in turn can improve a child’s ability to focus on tasks.

The new finding is the result of research by investigators at the University of California, San Francisco (UCSF). It is significant because it lets scientists know that Ritalin impacts and improves behaviour through two specific types of neurotransmitter receptors rather than just one. Neurotransmitters are chemicals that act as messengers to allow neurons to communicate with each other.

Previously experts knew that Ritalin enhanced the activity of the neurotransmitter dopamine receptor known as D2, which controls the ability to stay focused on a task. The new research shows that another dopamine receptor called D1, which is involved in the ability to learn and learning efficiency, is also affected by Ritalin. Apparently the drug produces these benefits by strengthening the ability of the neurons to communicate with each other at their meeting points, called synapses.

These new findings may allow researchers to develop more efficient drugs to treat ADHD and to improve the ability to focus and learn more efficiently, according to Antonello Bonci, MD, principal investigator at the Ernest Gallo Clinic and Research Center and professor of neurology at UCSF.