Modulation of Potassium Channels May Treat Symptoms in FXS, Study Finds

Compounds that can restore potassium balance in some brain regions may potentially treat sensory hypersensitivity and other symptoms in patients with fragile X syndrome, a new study suggests.

The study, “Modulators of Kv3 potassium channels rescue the auditory function of Fragile X mice,” was led by researchers from Yale University and published in the Journal of Neuroscience.

Fragile X syndrome is a genetic disease caused by occurrence of mutations on the FMR1 gene, which leads to impaired production of its coded FMRP protein.

Patients with fragile X syndrome can experience a wide range of symptoms, but one symptom that is particularly characteristic of the disease is hypersensitivity to auditory stimuli (sounds). Normal sound levels evoke abnormally high auditory response in these patients, and even ordinary environmental sounds can become unbearable for them.

Increased responses to sounds are likely influenced by alterations in neural (brain) networks, such as those in the auditory brainstem — the region of the brain that computes sound.

FMRP is known to regulate the presence and function of several ion channels involved in the activation of nerve cells and production of electrical impulses that transmit information, including sound data. So, loss of this protein has been shown to change the levels of ion channels brain cells.

In particular, ion channels present in the auditory brainstem have been shown to be impaired in mouse models of fragile X syndrome.

To better understand the impact of FMRP loss on the auditory brainstem response (ABR), researchers compared genetically engineered mice lacking fmr1 gene with healthy mice.

“The ABR is characterized by a series of electrical waves, labeled as waves I to V, representing the progressive transfer of the auditory signal from the periphery to the central nervous system,” researchers explained.

Results indicated that ABR wave I was reduced in mice with fragile X, but only at high sound levels. In contrast, ABR wave IV, which represents the synchronous activity of the auditory brainstem, was enhanced at all sound levels, suggesting that loss of FMRP changed the way the brain processes auditory signals.

They also found that sound stimuli triggered repetitive signals from nerve cells of the auditory brainstem in diseased mice rather than just a single signal, which is the normal response. Upon this discovery, researchers next investigated whether there was a way to curb these repetitive signals.

Kv3.1 is an ion channel present in neurons, including those in the auditory brainstem, and is known to activate high-frequency potassium-mediated signaling in response to sound stimuli. So, the team evaluated the effects of AUT2, a compound that regulates the activity of Kv3.1 ion channels, in mice with fragile X syndrome.

Administration of AUT2 showed to modulate brain signals and reduce the threshold of the stimulus that was required to fire off a signal, as well as to restore the normal wave IV pattern of the ABR.

Supported by these findings, the team believes that “modulation of Kv3.1 channel may have potential for treatment of sensory hypersensitivity in fragile X syndrome patients.”