Sodium ions could cause some Fragile X symptoms

Scientists believed that overactivity in a molecular pathway in the brain was an underlying cause of fragile X syndrome, but then two large-scale, multinational clinical trials aimed at inhibiting that pathway failed.

Now, researchers have another possible explanation for some of the symptoms of fragile X syndrome, the most common inherited cause of intellectual disability in the United States.

The study, published in Cell Reports, provides a new way of looking at the underlying causes of the syndrome and suggests new targets for treatment.

“We found another pathway that is dysregulated, that involves the same molecule implicated before—mGluR5—but in an entirely different way,” says Vitaly Klyachko, associate professor of cell biology and physiology at Washington University School of Medicine in St. Louis and the study’s senior author. “The previous theory wasn’t wrong, but it may be more complicated than anyone had thought.”

Hyperexcitable neurons

Fragile X syndrome affects about 1 in 4,000 people worldwide. There is considerable overlap between fragile X syndrome and autism: About 30 percent of people with fragile X are diagnosed with autism, and fragile X causes up to 6 percent of autism cases, making it the most common known cause of autism.

In fragile X syndrome, neurons are hyperexcitable, that is, they respond too easily when stimulated. “The circuits generate too much output relative to normal neurons,” Klyachko says.

How to reduce subtle symptoms of fragile X

Such overactive neuronal circuits are thought to lead to seizures and hypersensitivity to visual, auditory, and tactile stimuli. Such symptoms are common in people who have fragile X syndrome, as well as people with autism.

Fragile X syndrome is the result of genetic mutations that eliminate a protein called fragile X mental retardation protein. In the absence of that protein, other proteins involved in transmitting signals between neurons in the brain are overproduced, notably mGluR5, a receptor for the neurotransmitter glutamate.

The two failed clinical trials were based on the theory that too much of the protein mGluR5 leads to an excessive response to the excitatory neurotransmitter, which in turn leads to hyperexcitable neurons. Unfortunately, the two trials found that inhibiting mGluR5 did not improve symptoms in people with fragile X syndrome.

Sodium ions

Now, Klyachko and Pan-Yue Deng, an assistant professor of cell biology and physiology, have identified a separate mechanism that also results in neuronal hyperexcitability: an increase in the baseline flow of sodium ions into neurons.

With fragile X, brain cells can’t stop ‘talking’

Neurons generate an electrical spike when the flow of ions across the cell membrane rises above a set threshold. The researchers found that, in mice lacking the fragile X protein, mGluR5 provides a signal to modify a kind of sodium channel so that such channels persistently allow too much sodium to flow into neurons.

“The persistent sodium flow is too high so it’s easy for the neuron to cross the threshold and generate a spike,” Klyachko says. “The surprising part of this phenomenon is that it is dependent on mGluR5. It fits with previous research that shows mGluR5 is important for hyperexcitability, but in a different way than we had thought.”

Drugs that specifically target the persistent sodium ion flow, or current, have been approved by the Food and Drug Administration for treating epilepsy. Klyachko plans to test such drugs to see whether they reduce persistent sodium current down to normal levels, which he believes would make the neurons less excitable.

“Instead of targeting mGluR5, which is a very widespread molecule with many different functions, now we can target the persistent sodium current directly, using already approved drugs that are more specific and less likely to cause side effects,” Klyachko says. “We are initiating collaborative studies to see if we can improve some of the hyperexcitability defects we see in fragile X models, with the hope to eventually apply this new knowledge in patients with fragile X syndrome.”

The National Institute of Neurological Disorders and Stroke provided partial funding for the work.

Source: Washington University in St. Louis

The post Sodium ions could cause some Fragile X symptoms appeared first on Futurity.


Source: Futurity