Why different causes of autism respond to the same treatment

Several genetic disorders cause intellectual disability and autism.
Historically, these genetic brain diseases were viewed as
untreatable. However, in recent years neuroscientists have
shown in animal models that it is possible to reverse the
debilitating effects of these gene mutations. But the question
remained whether different gene mutations disrupt common
physiological processes. If this were the case, a treatment
developed for one genetic cause of autism and intellectual
disability might be useful for many others.
In a paper published today in the online edition of Nature
Neuroscience , a research team led by Mark Bear, the Picower
Professor of Neuroscience in MIT’s Picower Institute for
Learning and Memory, showed that two very different genetic
causes of autism and intellectual disability disrupt protein
synthesis at synapses, and that a treatment developed for one
disease produced a cognitive benefit in the other. The research
was performed by postdoc and lead author Di Tian, graduate
student Laura Stoppel, and research scientist Arnold Heynen, in
collaboration with scientists at Cold Spring Harbor Laboratory
and Roche Pharmaceuticals.
Researching the role of fragile X syndrome
One heritable cause of intellectual disability and autism is fragile
X syndrome, which arises when a single gene on the X
chromosome, called FMR1, is turned off during brain
development. Fragile X is rare, affecting one in about 4,000
individuals. In previous studies using mouse models of fragile X,
Bear and others discovered that the loss of this gene results in
exaggerated protein synthesis at synapses, the specialized sites
of communication between neurons.
Of particular interest, they found that this protein synthesis was
stimulated by the neurotransmitter glutamate, downstream of a
glutamate receptor called mGluR5. This insight led to the idea,
called the mGluR theory, that too much protein synthesis
downstream of mGluR5 activation gives rise to many of the
psychiatric and neurological symptoms of fragile X. Bear’s lab
tested this idea in mice, and found that inhibiting mGluR5
restored balanced protein synthesis and reversed many defects
in the animal models.
Different genes, same consequences
Another cause of autism and intellectual disability is the loss of a
series of genes on human chromosome 16, called a 16p11.2
microdeletion. Some of the 27 affected genes play a role in
protein synthesis regulation, leading Bear and colleagues to
wonder if 16p11.2 microdeletion syndrome and fragile X
syndrome affect synapses in the same way. To address this
question, the researchers used a mouse model of 16p11.2
microdeletion, created by Alea Mills at Cold Spring Harbor
Laboratory.
Using electrophysiological, biochemical, and behavioral
analyses, the MIT team compared this 16p11.2 mouse with
what they already had established in the fragile X mouse.
Synaptic protein synthesis was indeed disrupted in the
hippocampus, a part of the brain important for memory
formation. Moreover, when they tested memory in these mice,
they discovered a severe deficit, similar to fragile X.
Restoring brain function after disease onset
These findings encouraged the MIT researchers to attempt to
improve memory function in the 16p11.2 mice with the same
approach that has worked in fragile X mice. Treatment with an
mGluR5 inhibitor, provided by a team of scientists at Roche led
by Lothar Lindemann, substantially improved cognition in these
mice. Of particular importance, this benefit was achieved with
one month of treatment that began well after birth. The
implication, according to Bear, is that “some cognitive aspects of
this disease, previously believed to be an intractable
consequence of altered early brain development, might instead
arise from ongoing alterations in synaptic signaling that can be
corrected by drugs.”
Current research indicates that well over 100 distinct gene
mutations can manifest as intellectual disability and autism. The
current findings are heartening, as they indicate not only that
drug therapies might be effective to improve cognition and
behavior in affected individuals, but also that a treatment
developed for one genetic cause might apply more broadly to
many others.
This research was supported in part by the Howard Hughes
Medical Institute, the National Institute of Mental Health, the
Simons Foundation, the Simons Center for the Social Brain at
MIT, and the National Institute of Child Health and Human
Development.
This article is published in collaboration with MIT News . Publication
does not imply endorsement of views by the World Economic Forum.