Gene Knockout Scores a Fearless Mouse

Knocking out a gene in the brain’s fear hub creates mice unperturbed by situations that would normally trigger instinctive or learned fear responses, researchers funded, in part, by the National Institutes of Health have discovered. The findings may lead to improved treatments for anxiety disorders, they suggest.

The scientific team, led by National Institute of Mental Health (NIMH) grantee and Nobel Laureate Dr. Eric Kandel, Columbia University, Dr. Vadim Bolshakov, Harvard University, a grantee of the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Drug Abuse (NIDA), and Dr. Gleb Shumyatsky, Rutgers University, report on their study in the November 18, 2005 issue of Cell.

Fear memories are so essential for survival that they are easily formed and rarely lost. The workings of fear circuitry, centered in the amygdala, an almond-shaped structure deep in the brain, are well understood. Yet, relatively little is known about fear’s molecular basis, note the researchers.

The gene in the current study codes for stathmin, a protein that appears to be critical for the amygdala to rearrange connections and form fear memories. Stathmin normally controls this process by regulating the supply of microtubules, building materials that amygdala cells use to make structural adaptations that encode the memories. Runaway production of these building materials stymied construction of fear memories in a mouse strain molecularly engineered to lack stathmin, the researchers found.

They first showed that circuitry on the side of the amygdala known to be critical for fear learning is rich in stathmin. They then demonstrated that a cellular process critical for memory formation, long-term potentiation, is impaired there in stathmin knockout mice, due to the excess production of microtubules.

Compared to control animals, the stathmin knockout mice showed less anxiety (freezing) when they heard a tone that had previously been associated with a shock, indicating less learned fear. The knockout mice also were more prone to explore novel open space and maze environments, a reflection of less innate fear.

“Stathmin knockout mice can be used as a model of anxiety states of mental disorders with innate and learned fear components,” propose the researchers. “As a corollary, these animal models could be used to develop new anti-anxiety agents.”

This and related studies with other knockout mouse models suggest that subclasses of anxiety disorders will ultimately emerge, “each of which is likely to have a unique molecular signature and require distinctive pharmacological approaches,” they add.

“Whether stathmin is similarly expressed and pivotal for anxiety in the human amygdala remains to be confirmed,” noted NIMH director Dr. Thomas Insel. “Yet, this surprising discovery in the mouse hints at the potential for new treatment strategies likely still hidden in the vast uncharted territory of brain genetics.”

Also participating in the study: Shuichi Takizawa, Jamie Joseph, Rutgers University; Gael Malleret Stanislav Zakharenko, Svetlana Vronskaya, DeQi Yin, Columbia University; Keith Tully, Evgeny Tsvetkov, Harvard University; Ulrich Schubart, Albert Einstein College of Medicine.

In addition to the NIH, the research was also supported by NARSAD, NAAR, The Cure Autism Now Foundation, the New Jersey Governor’s council on Autism, the G. Harold and Leila Y. Mathers Charitable Foundation, the Whitehall Foundation, and the Esther A. & Joseph Klingenstein Fund.


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