Potassium Channel Modulators to Treat Fragile X

With $246,000 in funding from FRAXA over 2012-2014, the Yale University team of Leonard Kaczmarek, PhD, showed that loss of FMRP leads to an increased Kv3.1 potassium currents and decreased Slack potassium currents in neurons. Both of these changes impair timing of action potentials in auditory neurons (and likely others throughout the brain). The team also found that the firing pattern of neurons in response to repeated stimulation is severely abnormal in Fragile X mice. Based on these results, they are collaborating with the UK-based company Autifony to develop and test advanced compounds which may reverse these deficits.

$246,000 Grant
Leonard Kaczmarek, PhD
Principal Investigator
Yale University
2012-2014 FRAXA Research Grant
$246,000 over 3 Years

Loss of the messenger RNA-binding protein FMRP, which causes Fragile X syndrome, is associated with hypersensitivity to a variety of sensory stimuli, particularly sound. This sensitivity occurs because the excitability of groups of neurons in the brain is increased. Such over-excitability may also contribute to other features of Fragile X syndrome, such as the increased incidence of seizures in childhood and an inability to concentrate on or learn very fine motor tasks.

A variety of work has demonstrated that increased excitability occurs because FMRP normally controls a class of proteins called potassium channels. Potassium channels are key controllers of how intensely a neuron responds to stimulation and how accurately a neuron can follow different patterns of stimulation. The Kaczmarek group has been investigating pharmacological agents that modify these potassium channels and that are likely to prove to be therapeutic in Fragile X syndrome.

The first type of potassium channel implicated in Fragile X syndrome is called the Kv3.1 channel. This protein is normally required for neurons to generate electrical impulses at very high rates (many hundreds of times a second, as is required for normal hearing). When FMRP is absent, levels of Kv3.1 increase in the brain, and this allows neurons to fire at rates that are inappropriately high for the stimulation they are receiving.

In collaboration with a company, Autifony, the Kaczmarek group is studying drugs that directly counteract the effects of the increased Kv3.1 protein levels.

A second potassium channel, termed Slack, becomes reduced when FMRP is absent. A key role that Slack plays in the brain is to enhance the accuracy with which a neuron responds to its inputs, such as those coming from sensory organs. Slack normally binds directly to FMRP and this mutual interaction is required to maintain the activity of Slack. Thus neurons with low Slack activity are likely to make mistakes in timing when responding to inputs, and genetic changes in Slack channels themselves have devastating effects on psychomotor development.

At present there are no known pharmaceutical compounds that act on Slack channels, and so the Kaczmarek group is using novel high-throughput drug screening techniques to discover new compounds that act to correct the abnormal firing patterns resulting from low Slack activity.

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