GABAA RECEPTORS: DEVELOPMENTAL INFLUENCE ON BEHAVIOR

描述(由申请人提供)：最近的许多研究强调GABA能系统与复杂神经回路的发展和维持密切相关，而复杂的神经元回路对生物体的行为成功至关重要。阐明GABAA受体在创建和维持这些复杂的行为网络中的参与性作用，是理解与发育障碍相关的病理生理学的基础。此外，越来越多的证据表明，GABA能系统可能在两种发育障碍中发挥作用：自闭症和安杰曼综合症。我们建议研究发育受损的GABAA受体系统对成熟的海马体和小脑产生的影响以及它们调节的行为。我们的工作假设是，在发育过程中扰乱包含β3亚单位的GABAA受体将对神经组织产生深远的影响，导致以后的生命中出现异常行为。为了验证我们的假设，我们建议研究GABAA受体发育中断对成年小鼠的行为影响。将评估的行为是那些在自闭症和安杰曼综合症中普遍受损的行为。这些包括注意力处理、社会互动、探索和刻板印象行为。此外，我们还将研究这种发育障碍对海马体和小脑的形态和神经药理学的影响。这两个区域在自闭症和安杰曼综合症中都表现出异常，对上述行为是必不可少的。拟议中的研究将涉及两个不同的小鼠模型：1)GABRB3基因(编码GABAA受体的Beta3亚基)从受孕到一生的遗传中断；2)选择性的GABAA受体药物阻断，从胚胎第15天到出生后7天包含Beta3亚单位。这些研究的结果将为包括自闭症和Angelman综合征在内的各种发育障碍提供相关的见解。这项建议解决了几个关于神经发育对行为的影响的基本重要问题。

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.