Anis Contractor, PhD—Northwestern University
Rescuing cellular and cognitive deficits in FRX by restoration of chloride homeostasis

Anis Contractor, PhD, Principal Investigator (2005 to Present)
Diya Zhang, PhD, FRAXA Postdoctoral Fellow
Qionger He, PhD, Postdoctoral Fellow (2013)

FRAXA Awards:

$45,000 in 2013
$17,000 in 2008
$50,000 in 2006
$55,000 in 2005


During development, the major inhibitory neurotransmitter GABA actually elicits an excitatory response at many synapses. At some point, the response to GABA switches to inhibition, a maturation process which is regulated by the cell’s maintenance of chloride ion concentrations. This developmental switch appears to malfunction in fragile X, with many cells retaining this immature excitatory response to GABA. This may explain why inhibitory function is deficient in the fragile X brain. This group will attempt to rescue this abnormality in maturation of GABA responses by manipulating chloride concentrations with the available drug bumetanide.
Rescuing cellular and cognitive deficits in FRX

by Anis Contractor and Qionger He, 5/1/2013

The known genetic basis of fragile X syndrome has provided an opportunity to generate animal models in order to understand the cellular, synaptic and circuit alterations in fragile X. These studies have informed us of the underlying basis for the cognitive, sensory and behavioral deficits of the disorder. 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. Our ability to study this in detail in the mouse model will enable us to draw conclusions about the potential ways to target treatments.

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 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 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.

Rescuing Synaptic Function in Fragile X with Mutant AMPA Receptors

by Anis Contractor, 8/1/2008

Fragile X syndrome is the most common form of inherited human mental retardation and the single largest known genetic cause of autism. In our preliminary studies we have found that the maturation of neurons and synapses in the sensory cortex of the Fragile X mouse model is delayed. This altered synaptic maturation may result in disturbances in sensory processing, and thus be responsible for the behavioral alterations that reflect the way in which Fragile X sufferers perceive their environment.

A prevailing hypothesis posits that dysregulated group I metabotropic glutamate receptor (mGluR) signaling may underlie many of the neuronal phenotypes associated with the disease. In order to determine if reducing mGluR signaling may reverse synaptic maturation deficits, we have generated a novel mouse model in which we can inactivate the gene encoding a metabotropic glutamate receptor, mGluR5, in a temporally and spatially controlled manner on the Fragile X mouse model background. In this study we will determine whether reducing the expression of mGluR5 in the cortex of Fragile X mice reverses the aberrant synaptic development in the somatosensory cortex. Furthermore this novel mouse strain will be useful for determining whether other Fragile X related symptoms and cellular neuronal alterations can be reversed by the genetic inactivation of mGluR5.