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Children with Autism Have Extra Synapses in
Brain
May be possible to prune synapses with drug
after diagnosis
August 21, 2014 - Posted in:
Neurology, Neuroscience, Psychiatry
NEW YORK, NY (August 21,
2014) —
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.
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“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 the 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.
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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.”
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