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Abstract Details

Deficits in Tonic Inhibition May Contribute to Motor and Behavioral Abnormalities in Angelman Syndrome and Fragile X Syndrome
Child Neurology and Developmental Neurology
Child Neurology and Developmental Neurology Posters (7:00 AM-5:00 PM)
017
Examine the role of extrasynaptic gamma-aminobutyric acid (GABA) receptors in the pathophysiology of select neurodevelopmental disorders.
Tonic inhibition contributes to the regulation of neuronal excitability and is thought to play a fundamental role in maintaining signal fidelity across neuronal networks (Duguid et al. 2012). Extrasynaptic (δ-subunit–containing) GABAA receptors mediate tonic inhibition via persistent Cl- flux (Brickley and Mody, 2012). Reduced activity at these receptors caused by decreased extrasynaptic GABA concentrations may contribute to the pathophysiology of two genetic neurodevelopmental diseases, Angelman syndrome (AS) and fragile X syndrome (FXS; Egawa et al., 2012; Deidda et al., 2014). Both syndromes are characterized by severe developmental delay, intellectual disability, maladaptive behaviors including hyperactivity and anxiety, epilepsy, and sleep disorders.
Evaluate clinical and pre-clinical evidence supporting a role for impaired tonic inhibition in AS and FXS.
In a mouse model of AS, increased expression of GABA transporter type-1 resulted in lower endogenous GABA levels, decreased tonic inhibition, and motor function deficits. The selective extrasynaptic GABA receptor agonist gaboxadol increased tonic holding currents in hippocampal, cerebellar and cerebral cortical neurons, decreased ataxia and improved rotarod performance. Gaboxadol also normalized anxiety-like and aggression behaviors in an animal model of FXS.  Clinical studies of adolescents and adults with AS (STARS trial) and FXS (ROCKET trial) show improvement with gaboxadol in global outcomes as measured by the Clinical Global Impression scales. Additionally, gaboxadol treatment was associated with reductions in abnormal EEG activity in AS and improvements in anxiety and hyperactivity in FXS.
Extrasynaptic GABAA receptor signaling influences tonic inhibition under physiologic and pathophysiologic conditions. Nonclinical and clinical studies provide translational evidence that restoration of deficient extrasynaptic GABAA receptor signaling in AS and FXS ameliorates impaired tonic inhibition and functional outcomes.
Authors/Disclosures
Tom Parry
PRESENTER 		Tom Parry has received personal compensation for serving as an employee of Ovid Therapeutics Inc. Tom Parry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boehringer Ingleheim. Tom Parry has received personal compensation in the range of $0-$499 for serving as a Grant Reviewer with NIH.
No disclosure on file
No disclosure on file
No disclosure on file
Elizabeth M. Berry-Kravis, MD, PhD (Rush University Medical Center) The institution of Dr. Berry-Kravis has received research support from NIH. The institution of Dr. Berry-Kravis has received research support from Ionis. The institution of Dr. Berry-Kravis has received research support from Zynerba. The institution of Dr. Berry-Kravis has received research support from Roche. The institution of Dr. Berry-Kravis has received research support from CDC. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. The institution of Dr. Berry-Kravis has received research support from GeneTx. The institution of Dr. Berry-Kravis has received research support from Angelman Syndrome Foundation. The institution of Dr. Berry-Kravis has received research support from Acadia. The institution of Dr. Berry-Kravis has received research support from Ultragenyx. The institution of Dr. Berry-Kravis has received research support from Mallinckrodt. The institution of Dr. Berry-Kravis has received research support from Together Strong Foundation. The institution of Dr. Berry-Kravis has received research support from Zevra. The institution of Dr. Berry-Kravis has received research support from Taysha. The institution of Dr. Berry-Kravis has received research support from Tetra. The institution of Dr. Berry-Kravis has received research support from Neuren.
Alexander Kolevzon Alexander Kolevzon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ovid Therapeutics. Alexander Kolevzon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Alexander Kolevzon has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ovid Therapeutics. Alexander Kolevzon has received stock or an ownership interest from Ovid Therapeutics. The institution of Alexander Kolevzon has received research support from AMO Pharma. Alexander Kolevzon has received publishing royalties from a publication relating to health care.