CHILDREN WITH AUTISM. EXTRA SYNAPSES IN BRAIN
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 behaviors 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 behavior 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.
During normal brain
development, a burst of synapse formation occurs in infancy, particularly in
the cortex, a region involved in autistic behaviors; 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 behaviors."
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 behavior, 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."
The paper is titled,
"Loss of mTOR-dependent macroautophagy causes autistic-like synaptic
pruning deficits." Other authors are: Kathryn Gudsnuk, Sheng-Han Kuo,
Marisa L. Cotrina, Gorazd Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen
Kanter, Candace Castagna, Ai Yamamoto, Ottavio Arancio, Bradley S. Peterson,
Frances Champagne, Andrew J. Dwork, and James Goldman from CUMC; and Zhenyu Yue
(Icahn School of Medicine at Mount Sinai). Marisa Cotrina is now at the
University of Rochester.
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