Stanford Scientist`s New Findings of Autism-Associated Synapse Alterations Lead to Coveted NIH Grant

STANFORD, Calif.--(Business Wire)--
A Stanford University School of Medicine researcher has pinpointed the mechanism
by which a gene associated with both autism and schizophrenia influences
behavior in mice. And just recently, he received a $1.65 million government
grant to expand his efforts to include many more such genes.

In a study to be published online on Oct. 12 in the Proceedings of the National
Academy of Sciences, a team led by Thomas Sudhof, MD, the Avram Goldstein
Professor in the School of Medicine and professor of molecular and cellular
physiology, characterized key neurophysiological changes wrought by the deletion
of a particular gene in bioengineered mice. The team further identified
behavioral changes in the mice that are similar to some symptoms of autism and
schizophrenia.

The boundaries separating cognitive disorders including autism, schizophrenia,
depression and obsessive-compulsive disorder are not sharply drawn. In all of
these overlapping disorders, mutations in not one but hundreds of genes appear
to be able to cause the symptoms, suggesting an unprecedented heterogeneity that
has baffled scientists in the field.

For example, autism - a term often used to cover a group of related disorders -
is highly heritable, and researchers have identified a large number of gene
mutations associated with the disorders on this spectrum. However, no single
gene mutation has been found to account for more than a small fraction of
patients, though each mutation appears to be able to cause the disorder.

"One of the most perplexing things about autism is the heterogeneity of the
disease," said Sudhof, who is also a Howard Hughes Medical Institute
investigator. "Autism might be one disease, or it might be thousands of
diseases."

There is much confusion about what constitutes autism. While clinicians have
defined it by a variety of behavioral symptoms, other researchers have tried to
define it genetically. Sudhof is taking a different route in which he hopes to
puzzle out, at the physiological level, what all of these genes are doing.

Sudhof suspects that, while the number of different genes involved is large, the
protein products of these genes participate in a much smaller number of common
pathways. Thus, two genes may encode two proteins that seem totally unrelated
but, in fact, interact closely. A deficiency in either`s function could result
in the same outward defect.

Several large, independent genetic studies have shown that one gene whose
deletion occurs in about 0.5 percent of autism cases, but not at all in healthy
people, encodes a protein called neurexin-1alpha - one of a family of molecules,
collectively known as neurexins, that Sudhof discovered about 20 years ago.

One-half of a percent might not sound like much, but that`s more than most other
genes contributing to autism, Sudhof said. Given current estimates that upwards
of 673,000 American children have autism, several thousand of them carry the
deletion.

"Because of our longstanding interest in neurexin-1alpha, we already had mice
that were bioengineered to be lacking in neurexin-1alpha," said Sudhof. "So we
decided to look closely at those mice to see whether this genetic deficiency led
to any changes in communication between neurons and, if so, whether the
disrupted or altered communication was correlated with any observable behavioral
abnormalities reminiscent of those associated with human cognitive disorders
such as autism or schizophrenia."

The investigators compared a particular area in mutant mice`s brains with their
counterparts in a control group of normal mice and made several observations. In
this brain region (and presumably others as well, Sudhof noted) the mutant mice
had alterations in their synapses-the gaps between nerve cells where signals are
transmitted from one cell to another, in the aggregate determining the complex
circuitry that underpins how we think, feel and move.

The defect, moreover, was confined to one of the two broad classes of synapses:
excitatory, as opposed to inhibitory. "This selective change in the strength of
one type of synapse, but not the other type, alters the balance between the
two," said Sudhof.

Just as autistic or schizophrenic patients are in many respects normal, mice
lacking the neurexin-1alpha gene were not grossly dysfunctional or
survival-challenged. "The deletion didn`t leave the mice unable to eat or to
learn or to mate and procreate. If anything, they were actually better than the
control mice at executing tasks requiring motor coordination," such as balancing
atop a rotating rod without falling off, Sudhof said.

Importantly, though, the mutant mice exhibited discrete behavioral
differences-repeated stereotypical behaviors such as self-grooming, impaired
nest-building activity and so forth - suggestive of those associated with autism
or schizophrenia, according to Sudhof.

Having demonstrated that the neurophysiological effects of neurexin-1alpha - a
gene strongly implicated in autism and schizophrenia - correspond to behavioral
abnormalities reminiscent of these cognitive disorders, Sudhof plans to use a
new grant awarded by the National Institutes for Health to expand his search.

The NIH had put aside $60 million of its allocation as part of the economic
stimulus package specifically for research on autism, and Sudhof`s proposal was
chosen amid heavy competition.

He and his colleagues in the Stanford Institute for Neuro-Innovation and
Translational Neurosciences intend to use the grant to find out if other genes
(such as those just identified in a study published in Nature on Oct. 7) affect
the nervous system. The investigators will use established techniques to
inactivate or increase the activity of 81 autism-associated genes in cultured
mouse neurons, and then assess whether these changes affect neural development,
synapse density and synapse function. If any of these effects are found, the
gene modifications will be tested in whole mice.

The study`s first author was Mark Etherton, an MD/PhD student in Sudhof`s
laboratory. Funding for the study was provided by the National Institute for
Mental Health and by the Simons Foundation.

The Stanford University School of Medicine consistently ranks among the nation`s
top 10 medical schools, integrating research, medical education, patient care
and community service. For more news about the school, please visit
http://mednews.stanford.edu. The medical school is part of Stanford Medicine,
which includes Stanford Hospital & Clinics and Lucile Packard Children`s
Hospital. For information about all three, please visit
http://stanfordmedicine.org/about/news.html.

Stanford University School of Medicine
Bruce Goldman, 650-725-5371 (Print Media)
goldmanb@stanford.edu
M.A. Malone, 650-723-6912 (Broadcast Media)
mamalone@stanford.edu

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