The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

• Published in: Neuron (Cambridge, Mass.) Vol. 86; no. 5; pp. 1119 - 1130
• Main Authors: Braat, Sien, Kooy, R. Frank
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.06.2015
• Subjects: Animals; Child Development Disorders, Pervasive - drug therapy; Child Development Disorders, Pervasive - genetics; Child Development Disorders, Pervasive - metabolism; Developmental Disabilities - drug therapy; Developmental Disabilities - genetics; Developmental Disabilities - metabolism; Drug Delivery Systems - trends; Fragile X Syndrome - drug therapy; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; GABA Modulators - administration & dosage; GABA Modulators - metabolism; Humans; Nervous System Diseases - drug therapy; Nervous System Diseases - genetics; Nervous System Diseases - metabolism; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Rett Syndrome - drug therapy; Rett Syndrome - genetics; Rett Syndrome - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.03.042

Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials. In this Perspective, Braat and Kooy argue that the GABAergic system is an excellent therapeutic target for neurodevelopmental disorders, including autism and intellectual disability, as it is disturbed in many and because pharmacological intervention is on the shelf.