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.