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.
| DeLorey, Timothy M; Sahbaie, Peyman; Hashemi, Ezzat et al. (2011) Somatosensory and sensorimotor consequences associated with the heterozygous disruption of the autism candidate gene, Gabrb3. Behav Brain Res 216:36-45 |
| DeLorey, Timothy M; Sahbaie, Peyman; Hashemi, Ezzat et al. (2008) Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behav Brain Res 187:207-20 |
| Ferguson, Carolyn; Hardy, Steven L; Werner, David F et al. (2007) New insight into the role of the beta3 subunit of the GABAA-R in development, behavior, body weight regulation, and anesthesia revealed by conditional gene knockout. BMC Neurosci 8:85 |
| Hashemi, Ezzat; Sahbaie, Peyman; Davies, M Frances et al. (2007) Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of locus coeruleus dendrites. Brain Res 1129:191-9 |
