|Gene Triggers Obsessive Compulsive Disorder-Like
Syndrome in Mice
Study Suggests New Treatment Targets
Using genetic engineering, researchers have created an obsessive-compulsive
disorder (OCD) — like set of behaviors in mice and reversed
them with antidepressants and genetic targeting of a key brain
circuit. The study, by National Institutes of Health (NIH) — funded
researchers, suggests new strategies for treating the disorder.
Researchers bred mice without a specific gene, and found defects
in a brain circuit previously implicated in OCD. Much like people
with a form of OCD, the mice engaged in compulsive grooming, which
led to bald patches with open sores on their heads. They also exhibited
anxiety-like behaviors. When the missing gene was reinserted into
the circuit, both the behaviors and the defects were largely prevented.
The gene, SAPAP3, makes a protein that helps brain cells communicate
via the glutamate chemical messenger system.
“Since this is the first study to directly link OCD-like behaviors
to abnormalities in the glutamate system in a specific brain circuit,
it may lead to new targets for drug development,” explained Guoping
Feng, Ph.D., Duke University, whose study was funded in part by
the National Institute of Neurological Disorders and Stroke (NINDS),
the National Institute of Mental Health, and the National Institute
of Environmental Health Sciences (NIEHS). “An imbalance in SAPAP3
gene-related circuitry could help explain OCD.”
Feng, Jeffrey Welch, Ph.D., Jing Lu, Ph.D., William Wetsel, Ph.D.,
Nicole Calakos, M.D., Ph.D., and colleagues report on their discovery
in the August 23, 2007, issue of Nature.
“This serendipitous discovery illustrates how pursuit of basic
science questions can provide important insights with promising
clinical implications into poorly understood diseases,” said NINDS
director Story C. Landis, Ph.D.
“Ultimately, the challenge will be to translate what we learn
from this stunning new genetic animal model into help for the 2.2
million American adults haunted by unwanted thoughts and repetitive
behaviors,” added NIMH director Thomas R. Insel, M.D., who conducted
clinical studies on OCD earlier in his career.
Previous studies of OCD had implicated a circuit in which the
striatum, which straddles the middle of the brain, processes decisions
by the cortex, the executive hub at the front of the brain. But
exactly how circuit communications might go awry remained a mystery,
and glutamate was not a prime suspect.
Nor were Feng and colleagues initially interested in OCD. Rather,
they sought to understand the function of the protein made by the
SAPAP3 gene, which is involved in glutamate-mediated communications
in the cortex-striatum circuit. To find out how it worked, they
used genetic engineering to generate SAPAP3 knockout mice.
The mice seemed normal at first, but after four to six months,
all developed telltale bald patches of raw flesh on their faces,
caused by compulsive scratching. Videotapes confirmed that the
sores were self-inflicted — grooming behavior gone amok.
“We were surprised by the magnitude of this phenomenon,” recalled
Feng. “The parallels with OCD were pretty striking.”
In a series of behavioral tests, his team determined that the
SAPAP3 knockout mice also showed anxiety-like behaviors, often
associated with OCD. They were slower to venture into — and
quicker to exit — risky environments. And like their human
counterparts, the animals responded to treatment with a serotonin
selective reuptake inhibitor (fluoxetine), which reduced both the
excessive grooming and anxiety-like behaviors.
SAPAP3 is the only member of a glutamate-regulating family of
proteins that is present in large amounts in the striatum. It is
part of the machinery at the receiving end of the connections between
brain cells, where the neurotransmitter binds to receptors, triggering
increased activity among the cells.
The researchers found that lack of SAPAP3 genes dampened the increased
activity usually caused by glutamate and stunted the development
and functioning of circuit connections.
When the researchers injected the striatum of seven-day-old knockout
mice with a probe containing the SAPAP3 gene, it protected them
from developing the OCD and anxiety-like behaviors 4 to 6 months
later and corrected the circuit dysfunction. This confirmed that
the absence of the SAPAP3 gene in the striatum was indeed responsible
for the OCD-like effects.
The findings suggest that anxiety-related behavior may stem from
the striatum, which serves as a pivotal link between the cortex
and emotion hubs. The researchers note that recent genetic studies
of OCD have hinted at involvement of glutamate-related mechanisms.
Feng’s team is also looking beyond the SAPAP3 gene to other related
genes in the circuit that could lead to similar behavioral problems.
They are exploring how the SAPAP3 gene affects neural communications
and how it works at the molecular level — with an eye to
possible applications in drug development. Collaborating clinical
investigators are exploring whether specific variants of the SAPAP3
gene in humans may be related to OCD spectrum disorders, such as
trichotillomania, or obsessive hair pulling — a human syndrome
also characterized by bald patches on the head.
Also participating in the research were: Nicholas Trotta, Joao
Peca, Catia Feliciano, Ramona Rodriguiz, Meng Chen, Duke University;
Jin-Dong Ding, Richard Weinberg, University of North Carolina;
J. Paige Adams, Serena Dudek, NIEHS; Jianhong Luo, Zhejiang University,
The research was also funded, in part, by McKnight and Harwell
SAPAP3 knockout mouse has a raw bald patch on its face from
compulsive grooming behavior.
Source: Guoping Feng, Ph.D., Duke University
For more information:
Obsessive-compulsive disorder (OCD) http://www.nimh.nih.gov/healthinformation/ocdmenu.cfm
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the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
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