Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. The cause, which has been well-studied, is the loss of fragile X mental retardation protein (FMRP)—a genetic mutation that largely eliminates the fragile X protein.
The fragile X protein modulates neuronal functions, including neurons within the GABAergic system that regulates the activity of neural circuits. GABAergic system dysfunction is one of the hallmarks of FXS, yet the underlying mechanisms remain poorly understood. Experimental therapies designed to reset the system by compensating for the missing protein’s functions have not been effective in clinical trials.
Now, researchers have identified a previously unknown role for the fragile X protein in the GABAergic system. They have shown that the protein regulates the opening and closing of the GABA-A receptor in neurons from the hippocampus, thereby influencing how such neurons process information, a central part of learning and memory.
The findings indicate that the fragile X protein’s role is more complex than previously thought, and that finding effective therapies may depend on a more nuanced understanding of the myriad ways the loss of this protein affects the brain.
This work is published in Cell Reports in the article, “FMRP regulates GABAA receptor channel activity to control signal integration in hippocampal granule cells.”
“People think that since fragile X is related to the loss of a single protein, it is a simple disease that we can quickly understand and fix,” said Vitaly Klyachko, PhD, professor of cell biology & physiology at Washington University School of Medicine. “But the reality is that the more we study, the more we understand it’s not simple at all. I think part of the reason why clinical trials fail may be because we don’t really understand what’s going on very well. It is possible that we need to fix more than one mechanism at the same time for patients to see any meaningful improvement.”
The GABAergic system is based on the transmission of gamma aminobutyric acid (GABA) from one neuron to another. An overactive GABAergic system puts people to sleep; an underactive one is linked to depression, anxiety, and epileptic seizures.
To better understand the role of fragile X protein in the GABAergic system, Klyachko and Pan-Yue Deng, MD, PhD, associate professor of cell biology & physiology at Washington University School of Medicine, studied neurons from the brains of mice with and without the fragile X protein.
The researchers found that fragile X protein regulates single-channel activity of GABAAR in dentate granule cells and that this interaction regulates tonic inhibition and excitability of those cells. In addition, they found that the fragile X protein interacts with at least one GABAAR subunit—the α5.
“The fragile X protein directly interacts with receptors that play a major role in the way neurons process information,” Klyachko said. “This is an additional function for the fragile X protein, and it may be an important one. These neuronal receptors are everywhere, and they control many critical brain functions.”
But Klyachko cautions against assuming that these findings can be easily translated into therapies for people living with fragile X syndrome. The GABAergic system is complex, and small tweaks can have unexpected and far-reaching effects on brain function, he said.
“I think there is a very strong desire—an understandable one—to immediately translate each discovery into a clinical trial,” Klyachko said. “But if we don’t understand all of the functions this protein has and we try to go after one specific mechanism, it may destabilize the other ones, and the end result is that people don’t get better. An entirely different approach to treating this disease may be possible, but I think we need to first understand much more about how it works. This is just the first stepping stone in a new direction.”
