New Protein Therapy Promises Drug-Free Behavior Modification

The protein works by targeting excitatory and inhibitory synapses.

by Kastalia Medrano
Donald B. Arnold

Scientists at the University of Southern California have developed a means of modifying brain activity and behavior — one that uses the brain’s own synaptic processes as opposed to psychiatric drugs. Using a protein dubbed GFE3, researchers were able to specifically target the inhibitory and excitatory proteins and effectively “hijack” the natural process that switches them on or off, affecting cell memory and behavior. Protein-based therapies are relatively new for all sorts of other diseases — like cancer — so it’s not quite clear yet how far it’ll be able to progress. But the potential here is massive.

Protein-based therapies are considered a potential step up from psychiatric drug therapies because of the way they work. Whereas protein therapies target specific cell types, traditional drugs carpet bomb everything, degrading and affecting cells that just happen to be near the problem.

“The big problem with any of these protein-based therapeutics is that it’s very hard to get those genes into humans,” study lead author Donald B. Arnold, a professor of biological sciences at the USC Dornsife College of Letters, Arts, and Sciences, tells Inverse. “So if someone figured out a safe way of putting a virus into the human brain, then you could start talking about this as a therapeutic. But that’s just the problem with gene therapy in general. That being said, this thing works so cleanly, and without any side effects. For diseases where the general problem is with an imbalance of excitation and inhibition, this is a very precise tool that can go in and hit only the cells you want to hit, and dial inhibition and excitation either up or down.”

The study’s authors first developed the “finger” — the part that specifically attaches to the synapse — more than five years ago and have been working to attach the second component, the E3 ligase, which is what allows the protein to be degraded, for the past two years or so.

Arnold and his colleagues will now focus on collaborating with scientists studying brain circuitry; they’re interested in what’s actually producing the pattern of activity they see from these particular cells. A male mouse, for example, can be made aggressive by putting it in close proximity to another male mouse — so what role does inhibition play in that? The answer has always been complicated because the results can include positive inhibitory feedback loops that are difficult to tell apart from excitatory feedback loops. But this new therapy enables researchers to target specific cells and knock out that network, cutting the wires in circuit diagram, so to speak, and revealing what the actual pattern of wiring is.

The paper also produced another, rather surprising result: Researchers were able to get rid of inhibitory synapses, but when they halted the expression of the proteins, the synapses grew back. The protein doesn’t degrade the target; it degrades itself. It’s an extremely intriguing phenomenon that prompts further research questions: How does the cell know it’s missing its inhibitory synapses? What is the mechanism for putting them back?

The balance — or rather, imbalance — of excitation and inhibition is key to such diseases as autism, schizophrenia, epilepsy, addiction — anything where the cell can’t figure out that it needs more inhibition. So understanding how the cell decides it’s short on inhibition is hugely important for research in these fields, and there’s very little known at the moment.

This new system is so powerful that it even survives the brain’s fast-paced cell turnover process. Neurons don’t turn over — we have those for life — but proteins do. Your brain’s proteins are constantly being created and degraded, and by the end of each week or so, it comprises completely different molecules than it did the week before.

“Manipulating this system has a whole lot of potential,” Arnold said. “When the day comes and they develop a safe way of putting this in a human, it’ll be ready to roll.”