GABA System Alterations and Fragile X Syndrome

GABA 系统改变和脆性 X 综合征

• 批准号: 9008056
• 负责人: CAROLYN R HOUSER
• 金额: $ 31.64万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008056
• 关键词: Action Potentials; Address; Anti-Anxiety Agents; Anxiety; Axon; Behavioral; Benzodiazepines; Brain; Brain region; Child; Climacteric; Development; Diazepam; Disease; Electrophysiology (science); Employee Strikes; Epilepsy; FMR1; 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; anxiety-related behavior; 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 anxiety

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.

描述（由申请人提供）：脆性 X 综合征 (FXS) 是遗传性认知障碍的最常见形式，患有这种疾病的儿童通常会出现其他行为和神经问题，包括焦虑增加、自闭倾向、多动症和癫痫。由于 GABA 系统在参与这些行为表型的神经系统的调节中发挥着重要作用，因此 FXS 中可能存在 GABA 系统缺陷。虽然 GABAA 受体 (GABAAR) 的改变已被识别，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，该项目的总体目标是检验以下假设：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，并且这些变化与功能缺陷相关，包括神经元兴奋性增加和焦虑相关行为改变。具体目标 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 12 亚基的变化。重要的是，我们将在野生型和 Fmr1 敲除小鼠的整个产后早期发育过程中跟踪 12 亚基的表达模式，以便识别可能与 FMRP 功能丧失相关的早期变化，并在生命后期可能变得明显的潜在补偿变化之前发生。具体目标 2 将鉴定可能与 Fmr1 敲除小鼠中 12 亚基表达改变相关的功能缺陷。体外电生理学研究将用于评估齿状颗粒细胞轴突起始段的 GABA 功能，其中 12 个亚基通常很突出，并且含有 12 个亚基的 GABAAR 的丢失可能会影响轴突电位的产生并增加颗粒细胞的兴奋性。行为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，这种作用可能会因 Fmr1 缺陷小鼠中 GABAAR 亚基的变化而改变。具体目标 3 将鉴定 Fmr1 敲除小鼠中 GABAAR 4 亚基的表达和定位的变化，并确定这些变化是否反映在齿状回神经类固醇的强直抑制及其调节的变化中。具体目标 4 将确定 GABAAR 相关的药物治疗是否会改善 Fmr1 敲除小鼠的一些行为变化和 GABAAR 亚基缺陷。这些研究将提供有关 FXS 小鼠模型出生后发育过程中 GABAAR 亚基变化的独特信息，并可为针对该疾病的新 GABAAR 亚基靶向治疗提供框架。