Chilled-out mice hold key to new treatments for psychological disorders

“Don’t make me angry. You wouldn’t like me when I’m angry,” the Hulk’s alter ego Bruce Banner famously said. Now researchers have made a discovery that might one day have implications for anyone considering Bruce as a potential house guest. The researchers have identified a brain receptor that malfunctions in overly hostile mice - a receptor that also exists in humans - and found a way to shut it down, offering the potential for the development of treatments for severe aggression.
The breakthrough by Marco Bortolato and Jean Shih from the University of Southern California’s (USC) School of Pharmacy, working with colleagues in Italy, builds on previous work by Bortolato and Shih, in which they identified a specific gene disposition resulting in low levels of the enzyme monoamine oxidase A (MAO A). They found that humans and mice with this congenital deficiency of the enzyme respond to stress with violent outbursts.

“The same type of mutation that we study in mice is associated with criminal, very violent behavior in humans,” Bortolato said. “But we really didn’t understand why that it is.”
To replicate elements of human pathological aggression in mice, the researchers combined low enzyme levels with stressful events early in life, such as trauma and childhood neglect.
“Low levels of MAO A are one basis of the predisposition to aggression in humans. The other is an encounter with maltreatment, and the combination of the two factors appears to be deadly: It results consistently in violence in adults,” Bortolato said.

Their research showed that extremely aggressive rodents lacking in MAO A required high levels of electrical stimulus to activate a specific brain receptor in the pre-frontal cortex known as NMDA. They add that, even when NMDA does work, it remains active for only a short period of time. Bortolato says that NMDA is thought to play a key role in helping people make sense of multiple, coinciding streams of sensory information.

“The fact that blocking this receptor moderates aggression is why this discovery has so much potential. It may have important applications in therapy,” Bortolato says. “Whatever the ways environment can persistently affect behavior – and even personality over the long term – behavior is ultimately supported by biological mechanisms.”

With pathological aggression a component in a number of common psychological disorders, including Alzheimer’s disease, autism, bipolar disorder and schizophrenia, the researchers are now studying the potential side effects of drugs that reduce the activity of the aggression receptor.
“Aggressive behaviors have a profound socioeconomic impact, yet current strategies to reduce these staggering behaviors are extremely unsatisfactory,” Bortolato said. “Our challenge now is to understand what pharmacological tools and what therapeutic regimens should be administered to stabilize the deficits of this receptor. If we can manage that, this could truly be an important finding.”