When it comes to developing drugs for mental illnesses, three confounding challenges exist:
Men and women experience them differently, with things like depression and anxiety far more common in females.
A drug that works for one person may not work for another, and side effects abound.
New CU Boulder research, published in the journal , sheds light on one reason those individual differences may exist. Turns out a key protein in the brain called AKT may function differently in males than females. The study also offers a closer look at where, precisely, in the brain things may go wrong with it, marking an important step toward more targeted and less harmful therapies.
鈥淭he ultimate goal is to find the kink in the armor of mental illness鈥攖he proteins in the brain that we can specifically target without impacting other organs and causing side effects,鈥� says Charles Hoeffer, an assistant professor of integrative physiology at the Institute for Behavioral Genetics. 鈥淧ersonalization is also key. We need to stop hitting every mental illness with the same hammer.鈥�
The stuff memories are made of
Discovered in the 1970s and best known for its potential role in causing cancer when mutated, AKT has more recently been identified as a key player in promoting 鈥渟ynaptic plasticity.鈥� That鈥檚 the brain鈥檚 ability to strengthen connections between neurons in response to experience.
鈥淟et鈥檚 say you see a shark and you鈥檙e scared and your brain wants to form a memory. You have to make new proteins to encode that memory,鈥� explains Hoeffer. 听
AKT is one of the first proteins to come online, cranking the gears up on a host of downstream proteins in that memory factory. Without it, researchers have suspected, we can鈥檛 learn new memories or extinguish old ones to make room for new, less harmful ones.
Previous studies have linked mutations in the AKT gene to a host of problems, from schizophrenia and post-traumatic stress disorder to autism and Alzheimer鈥檚.
We need to stop hitting every mental illness with the same hammer.鈥�
鈥揅harles Hoeffer
But, as Hoeffer鈥檚 previous research has discovered, not all AKTs are created equal:
Different flavors, or isoforms, function differently in the brain. For instance, AKT2 found exclusively in the star-shaped brain cells called astroglia, is often implicated 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 critical for learning and memory.
鈥淭hese subtle differences could be really important if you wanted to personalize treatments for people,鈥� explains Marissa Ehringer, an associate professor of integrative physiology who partnered with Hoeffer on some of the research.
How males and females differ
Three years in the making, the new study adds an important new wrinkle to the story. Following National Institutes of Health guidelines that in the past six years began to require researchers to include both male and female animals in studies, it looked closely at how male and female mice responded differently to the loss of various AKT isoforms.
鈥淲e found the difference between males and females to be so great it became the focus of our work,鈥� Hoeffer said. 鈥淚t was like night and day.鈥�
For instance, male mice whose AKT1 was functioning normally were much better than those missing the protein when it came to 鈥渆xtinction learning鈥濃�攔eplacing an old memory, or association, that鈥檚 not useful any more. (Imagine letting go of the memory of your favorite route home from work because you鈥檝e moved, or disassociating a loud sound with danger).
For female mice, it didn鈥檛 make much of a difference.
Far more research is needed and underway, but Hoeffer suspects many other key proteins in the brain share similar nuances鈥攚ith different flavors serving different purposes or acting differently in men and women.
With one in five U.S. adults living with mental illness and women as much as four times as likely to experience it听during their lifetimes, he hopes that by disentangling all those nuances, he can move the dial toward better, safer treatments.
鈥淭o help more people suffering from mental illness we need much more knowledge about the difference between male and female brains and how they could be treated differently,鈥� Hoeffer said. 鈥淭his study is an important step in that direction.鈥�
