With a $100,000 grant from FRAXA Research Foundation, Drs. Joshua Corbin and Molly Huntsman from the Children’s National Medical Center examined the role of a particular class of brain cells (inhibitory interneurons) that dampen excessive activity in the “emotional center of the brain” (the amydala). This inhibition is deficient in Fragile X, and so they are looked for ways to remedy this. This is particularly interesting to parents of children who are overly anxious and emotional. They worked with Dr. Walter Kaufmann, a clinician at Kennedy Krieger Institute in Maryland.
Rescue of GABAergic Transmission Defects in the Amygdala in the Fmr1-/- Mutant Mouse Model of Fragile X Syndrome
The proper functioning of neuronal circuits in the mature brain is dependent on maintenance of the normal balance between excitatory and inhibitory neuronal transmission. In Fragile X syndrome, there is an overexcitation within neuronal circuits, which manifests as alterations in brain function. Work in our laboratory was directed toward understanding and correcting deficiencies in inhibitory, GABAergic transmission in Fragile X syndrome. Toward this goal, we focused our studies on amygdala synaptic function and dysfunction in the Fmr1-/- knockout mouse model of Fragile X syndrome. The amygdala is a highly relevant and little examined brain region in relation to Fragile X syndrome pathogenesis. It performs a number of distinct functions, most prominently in the integration and processing of information with emotional salience, especially negative emotions such as fear. The amygdala is also involved in the regulation of attention and eye gaze, as well as modulation of anxiety state and social avoidance responses, most of which are abnormal in Fragile X Syndrome. Using a combination of mouse genetic and pharmacological approaches, this project was designed to rescue the abnormalities in inhibitory synaptic dysfunction in the amygdala in the Fmr1-/- knockout mouse.
The GABA(A) Receptor Agonist THIP Ameliorates Specific Behavioral Deficits in the Mouse Model of Fragile X Syndrome
Hyperactivity, hypersensitivity to auditory stimuli, and exaggerated fear are common behavioral abnormalities observed in individuals with Fragile X syndrome (FXS), a neurodevelopmental disorder that is the most common genetic cause of autism. Evidence from studies of the Fmr1 knockout (KO) mouse model of FXS supports the notion that impaired GABAergic transmission in different brain regions such as the amygdala, striatum or cerebral cortex is central to FXS behavioral abnormalities. This suggests that the GABAergic system might be an intriguing target to ameliorate some of the phenotypes in FXS. Our recent work revealed that THIP (gaboxadol), a GABA(A) receptor agonist, can restore principal neuron excitability deficits in the Fmr1 KO amygdala, suggesting that THIP may also restore some of the key behavioral abnormalities in Fmr1 KO mice. Here, we reveal that THIP significantly attenuated hyperactivity in Fmr1 KO mice, and reduced prepulse inhibition in a volume-dependent manner. In contrast, THIP did not reverse the deficits in cued fear or startle response. Thus, this study shows that enhancing GABAergic transmission can correct specific behavioral phenotypes of the Fmr1 KO mouse further supporting that targeting the GABAergic system, and specifically tonic inhibition, might be important for correcting or ameliorating some key behaviors in FXS.