NKCC1 Inhibitor Bumetanide Corrects Synaptic and Circuit Hyperexcitability in Fragile X Mouse Model

With $258,000 in grants since 2013 from FRAXA Research Foundation, Dr. Anis Contractor and Dr. Qionger He at Northwestern University found that the available drug bumetanide can correct altered GABA signalling in a mouse model of Fragile X syndrome.

“We found that if we gave this drug early in development, it not only corrected the development of synapses during the early critical period, it also corrected the sensory problems we saw in adult mice,” Contractor said. “It is possible that correcting chloride or correcting neurotransmitter signaling in humans could also have the same effect.”

Results Published: Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in Fragile X mice
Qionger He, PhD, and Anis Contractor, PhD
$258,200 Grants
Qionger He, PhD
FRAXA Fellow
Anis Contractor, PhD
Principal Investigator
Northwestern University
FRAXA Research Grants
$258,000 over 2013-2017

In this project we will test the hypothesis that alterations in inhibitory neurotransmission in the cortex during early development cause abnormal trajectories in the development of cortical circuits.

GABA is the major inhibitory neurotransmitter in the adult brain. In contrast, during early development this neurotransmitter excites neurons. In the cortex there is a well-defined time-point when GABA switches from this immature excitatory to the mature inhibitory form, that is critical to the normal development of neurons.

In preliminary studies we have determined that the timing of this switch from GABA excitation to inhibition is delayed in the cortex of the Fragile X mouse model. This altered timing could result in altered circuit development and ultimately could be linked to an increased propensity for seizures, hyper-arousal, and hypersensitivity to sensory stimuli.

We propose a simple way to correct this altered GABA signaling using a commonly used diuretic – bumetanide – that affects the balance of intracellular ions in neurons, and will thus promote the switch to the mature form of GABA signaling. This early correction of GABA signaling in the cortex can potentially have a dramatic effect on correcting the neuronal deficits associated with the disorder. We will test this possibility by testing whether behavioral alterations that have been observed in the Fragile X mouse model are rectified by chronic treatment, during cortical critical periods, with this drug. These studies will test a novel hypothesis about the mechanism for the altered development of synapses and circuits in the cortex, and potentially provide a new direction for treatment of Fragile X syndrome.

Previous Grant to this Team
$127,000 over 2005-2008
Qionger He, PhD, and Anis Contractor, PhD

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