GABAA RECEPTORS: DEVELOPMENTAL INFLUENCE ON BEHAVIOR

Molecular Research Institute, Palo Alto CA

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Abstract

DESCRIPTION (provided by applicant): Numerous recent studies have highlighted the GABAergic system's intimate involvement in the development and maintenance of the complex neuronal circuits vital to the behavioral success of an organism. Clarifying the participatory role that GABAA receptors have in creating and maintaining these complex behavioral networks is fundamental to understanding the pathophysiologies associated with developmental disorders. Furthermore, there is mounting evidence that the GABAergic system may play a role in two developmental disorders; autism and Angelman syndrome. We propose to study the resulting impact that a developmentally impaired GABAA receptor system has on the mature hippocampus and cerebellum and the behaviors they modulate. Our working hypothesis is that disrupting GABAA receptors, which contain the beta 3 subunit, during development will exert a profound effect on neural organization resulting in aberrant behaviors later in life. To test our hypothesis, we propose to study the behavioral ramifications in mature mice that arise from the developmental disruption of the GABAA receptor. Behaviors that will be assessed are those that are commonly impaired in both autism and Angelman syndrome. These include attentional processing, social interactions, exploration and stereotyped behavior. Additionally, we will also examine the consequences of this developmental disruption on the morphology and neuropharmacology of the hippocampus and cerebellum. Both regions exhibit abnormalities in autism and Angelman syndrome and are essential to the above behaviors. The proposed studies will involve two separate mouse models: 1) a genetic disruption of the gabrb3 gene (encoding the beta3 subunit of the GABAA receptor) from conception throughout life; 2) a selective pharmacological block of GABAA receptors that contain the beta3 subunit from embryonic day 15 through postnatal day 7. Results of these studies will provide pertinent insight into a variety of developmental disorders including autism and Angelman syndrome. This proposal addresses several issues of fundamental importance regarding the influence of neural development on behavior.