Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene triggers obsessive compulsive disorder-like syndrome in mice

23.08.2007
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.

Jules Asher | EurekAlert!
Further information:
http://www.nimh.nih.gov/healthinformation/ocdmenu.cfm
http://www.nlm.nih.gov/medlineplus/ency/article/001517.htm
http://www.niehs.nih.gov/

Further reports about: Genetic OCD Researchers SAPAP3 Striatum anxiety-like circuit compulsive glutamate

More articles from Life Sciences:

nachricht Warming ponds could accelerate climate change
21.02.2017 | University of Exeter

nachricht An alternative to opioids? Compound from marine snail is potent pain reliever
21.02.2017 | University of Utah

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Impacts of mass coral die-off on Indian Ocean reefs revealed

21.02.2017 | Earth Sciences

Novel breast tomosynthesis technique reduces screening recall rate

21.02.2017 | Medical Engineering

Use your Voice – and Smart Homes will “LISTEN”

21.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>