CU Boulder ‘s research discusses why psychiatric drugs only help some people

With regard to the development of drugs for mental illness, there are three challenging challenges:

• Men and women experience them differently, with things like depression and anxiety far more common in women.
• A drug that works for one person may not work for another, and side effects are plentiful.

CU Boulder’s new research, published in the journal eLIfe, sheds light on one possible reason for these individual differences. Turning out a major protein in the brain called AKT works differently in males than females.

The study also takes a closer look at where, in detail, the brain may go wrong, identifying an important step towards more focused and less harmful treatments.

The ultimate goal is to find the kink in the arsenal of mental illness – the proteins in the brain that we can target specifically without affecting other organs and causing side effects. Personalization is also important. We must stop all mental illness with one hammer. “

Charles Hoeffer, Associate Professor of Integrative Psychology at the Institute for Behavioral Genetics

Discovered in the 1970s and famous for its potential role in causing cancer when reversed, AKT has recently been identified as a major player in promoting “synaptic plasticity.” That is the ability of the brain to strengthen connections between neurons in response to experience.

“We say you see a shark and you are scared and your brain wants to create memory. You have to make new proteins to encode that memory,” Hoeffer explained.

AKT was one of the first proteins to come online, splitting the gears up on several proteins downstream in that memory factory. Without it, researchers suspect, we can’t learn new memories or delete old ones to make room for new, less harmful ones.

Previous studies have linked mutations in the AKT gene to a number of disorders, from schizophrenia and post-traumatic stress disorder to autism and Alzheimer’s.

However, as previous research by Hoeffer found, not all AKTs are created equal:

Different flavors, or isoform, work differently in the brain. For example, AKT2 found only in star-shaped brain cells called astroglia, is often involved in brain cancer.

AKT3 appears to be important for brain growth and development. And AKT1, in combination with AKT2 in the prefrontal cortex of the brain, appears to be essential for learning and memory.

“These subtle differences could be very important if you wanted to personalize treatments for people,” explained Marissa Ehringer, an associate professor of integrated psychology who was in a partnership. with Hoeffer on some of the research.

Three years on, the study adds a significant new dimension to the story. Following the guidelines of the National Institutes of Health which, in the past six years, required researchers to include male and female animals in studies, they looked closely at how different sex mice coped with loss. various AKT isoforms.

“We found that the difference between men and women was so great that it became the center of our work,” said Hoeffer. “It was like night and day.”

For example, male mice with AKT1 functioned normally, far better than those who missed the protein when it came to “learning to extinction” – replacing an old memory, or society, that is no longer useful. (Imagine forgetting your favorite way home from work because you’ve moved or eliminated loud noise with danger).

For female mice, it made little difference.

Much more research is needed and it is ongoing, but Hoeffer suspects many other key proteins in the brain share similar nuances – with different flavors serving different purposes or work differently in men and women.

With one in five U.S. adults living with a mental illness and women being as much as four times more likely to experience mental illness in their lifetime, he hopes by eliminating these nurses, he can shift the dial towards better and safer treatments.

“To help more people with mental illness we need to know a lot more about the difference between male and female brains and how they can be treated differently,” he said. Hoeffer. “This study is an important step in that direction.”