GABA System Alterations and Fragile X Syndrome

GABA 系统改变和脆性 X 综合征

• 批准号: 8234488
• 负责人: CAROLYN R HOUSER
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-20 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234488
• 关键词: Action Potentials; Address; Anti-Anxiety Agents; Anxiety; Axon; Behavior; Behavioral; Benzodiazepines; Brain; Brain region; Child; Climacteric; Development; Diazepam; Disease; Employee Strikes; Epilepsy; Fragile X Mental Retardation Protein; Fragile X Syndrome; GABA Receptor; Generations; Goals; Human; Hyperactive behavior; Impaired cognition; In Vitro; Inherited; Knockout Mice; Knowledge; Learning; Life; Lithium Chloride; Mediating; Memory impairment; Messenger RNA; Methods; Mission; Modeling; Mus; Neurologic; Neurons; Pattern; Performance; Pharmacological Treatment; Phenotype; Play; Predisposition; Prosencephalon; Protein Subunits; Public Health; Regulation; Research; Role; Seizures; Signal Pathway; Suggestion; Surface; Synapses; System; Testing; Wild Type Mouse; Work; base; behavior test; dentate gyrus; gamma-Aminobutyric Acid; granule cell; improved; mature animal; mouse model; neuronal excitability; neuroregulation; neurosteroids; novel; postnatal; protein function; receptor; response; sedative; social

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited cognitive impairment, and children with this disorder often have additional behavioral and neurological problems, including increased anxiety, autistic tendencies, hyperactivity and epilepsy. Since the GABA system plays an important role in regulation of the neural systems involved in these behavioral phenotypes, GABA system deficits could be present in FXS. While alterations in GABAA receptors (GABAARs) have been identified, knowledge of the regional and cellular localization of changes in GABAAR subunits remains very limited. Thus, the broad goal of this project is to test the hypothesis that expression and localization of specific subunits of the GABAAR are altered during postnatal development in a mouse model of FXS and that these changes are associated with functional deficits, including increased neuronal excitability and altered anxiety- related behavior. Specific Aim 1 will identify changes in the 12 subunit of the GABAAR in Fmr1 knockout mice that lack the Fragile X mental retardation protein (FMRP), using immunohistochemical methods. Importantly, the patterns of expression of the 12 subunit will be followed throughout early postnatal development in wild-type and Fmr1 knockout mice in order to identify early changes that could be associated with loss of FMRP function and precede potential compensatory changes that may become apparent later in life. Specific Aim 2 will identify functional deficits that could be associated with altered expression of the 12 subunit in Fmr1 knockout mice. In vitro electrophysiological studies will be used to assess GABAergic function at the axon initial segment of dentate granule cells where the 12 subunit is normally prominent and where a loss of 12 subunit-containing GABAARs could influence axon potential generation and increase granule cell excitability. Behavioral tests will be used to evaluate the anxiolytic and sedative effects of a classical benzodiazepine that could be altered in response to GABAAR subunit changes in Fmr1-deficient mice. Specific Aim 3 will identify changes in the expression and localization of the 4 subunit of the GABAAR in the Fmr1 knockout mouse and determine if such changes are reflected in alterations in tonic inhibition and its modulation by neurosteroids in the dentate gyrus. Specific Aim 4 will determine if GABAAR-related pharmacological treatment will ameliorate some of the behavioral changes and GABAAR subunit deficits in Fmr1 knockout mice. These studies will provide unique information about GABAAR subunit alterations during postnatal development in a mouse model of FXS and could provide a framework for new GABAAR subunit-targeted treatments for this disorder. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will provide new information about changes in GABA receptors during development in a model of Fragile X syndrome, the most common form of inherited cognitive impairment in humans. The project is relevant to NIH's mission because it could provide new views of the basic mechanisms underlying Fragile X syndrome and related disorders and suggest novel treatment approaches that could include targeting specific subunits of GABA receptors.

描述（由申请人提供）：脆性X综合征（FXS）是最常见的遗传性认知障碍形式，患有这种疾病的儿童通常会有额外的行为和神经问题，包括焦虑增加、自闭症倾向、多动和癫痫。由于GABA系统在调节参与这些行为表型的神经系统中起着重要作用，因此GABA系统缺陷可能存在于FXS中。虽然GABAA受体（GABAARs）的改变已经被确定，但对GABAAR亚基变化的区域和细胞定位的了解仍然非常有限。因此，本项目的主要目标是验证以下假设：在FXS小鼠模型中，GABAAR特定亚基的表达和定位在出生后发育过程中发生改变，这些变化与功能缺陷有关，包括神经元兴奋性增加和焦虑相关行为改变。Specific Aim 1将使用免疫组织化学方法，鉴定缺乏脆性X智力迟钝蛋白（FMRP）的Fmr1敲除小鼠中GABAAR的12个亚基的变化。重要的是，12亚基的表达模式将在野生型和Fmr1敲除小鼠的出生后早期发育过程中被跟踪，以确定可能与FMRP功能丧失相关的早期变化，并先于可能在以后的生活中变得明显的潜在代偿性变化。特异性Aim 2将确定Fmr1敲除小鼠中可能与12亚基表达改变相关的功能缺陷。体外电生理研究将用于评估齿状颗粒细胞轴突初始段的gabaar能功能，其中12亚基通常是突出的，并且12亚基含GABAARs的损失可能影响轴突电位的产生并增加颗粒细胞的兴奋性。行为学测试将用于评估经典苯二氮卓类药物的抗焦虑和镇静作用，这种药物可能会因fmr1缺陷小鼠的GABAAR亚基改变而改变。特异性Aim 3将确定Fmr1敲除小鼠中GABAAR的4个亚基的表达和定位的变化，并确定这种变化是否反映在齿状回张力抑制及其神经类固醇调节的变化中。特异性Aim 4将确定GABAAR相关的药物治疗是否会改善Fmr1基因敲除小鼠的一些行为改变和GABAAR亚基缺陷。这些研究将提供关于FXS小鼠模型出生后发育过程中GABAAR亚基改变的独特信息，并为针对该疾病的新的GABAAR亚基治疗提供框架。