Sensory Hypersensitivity in Fragile X Syndrome Due to Deficits in Tonic Inhibition Reversed by Neuroactive Steroids

神经活性类固醇逆转强直抑制缺陷所致脆性 X 综合征患者的感觉超敏反应

• 批准号: 9975520
• 负责人: Paul Andrew Davies
• 金额: $ 24.56万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975520
• 关键词: Acoustics; Allopregnanolone; Animal Model; Auditory; Auditory area; Auditory system; Biological Availability; Brain; Cell membrane; Cell surface; Chemosensitization; Coupled; Data; Development; Diagnosis; Disease; Electrodes; Epilepsy; Event; Exhibits; Exposure to; FMR1; Fragile X Syndrome; Functional disorder; Genotype; Hypersensitivity; Implant; Inherited; Intellectual functioning disability; Intervention; Ion Channel; Knockout Mice; Laboratories; Liquid Chromatography; Mass Spectrum Analysis; Measures; Medial geniculate body; Mediating; Membrane; Mus; Neurons; Oral; Output; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphorylation; Phosphotransferases; Process; Progesterone Receptors; Proteins; Seizures; Sensory; Serine; Severities; Signal Transduction; Site; Stimulus; Symptoms; Synapses; Testing; Thalamic structure; Therapeutic Uses; Work; auditory processing; auditory stimulus; autism spectrum disorder; habituation; improved; insight; neurodevelopment; neuronal circuitry; neuronal excitability; neurosteroids; novel; novel therapeutics; receptor; receptor expression; response; sensory stimulus; sound; targeted treatment; trafficking

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a major cause for a diagnosis of autism spectrum disorders. The symptoms of FXS include hypersensitivity to sensory stimuli, and seizures. The cause of FXS is a loss of the fragile X mental retardation protein (FMRP) yet the underlying pathways and mechanisms of these symptoms are poorly described. GABAA receptors (GABAARs) are major inhibitory ion channels in the brain. Studies from both FXS patients and animal models have revealed altered expression levels of GABAAR α4 subunits with a concomitant reduced efficacy of tonic inhibition, a non-synaptic type of inhibition important for determining the gain of the neuronal output, thus regulating the excitability and activity of neuronal circuits. Our preliminary data suggest that in Fmr1 KO mice there is a decrease in the phosphorylation of α4 subunits leading to decreased tonic current, and an increased excitation. The deficits of tonic inhibition are due to a disruption in trafficking of α4-containing GABAARs from extrasynaptic to synaptic sites. Both FXS patients and Fmr1 KO mice show auditory processing deficits making them hypersensitive to sound. Acoustic information is processed by thalamic auditory neurons in the medial geniculate body (MGB) as it ascends to the auditory cortex. Excitation of auditory thalamic neurons is controlled by tonic inhibition dependent upon GABAARs containing α4 subunits. Reduced tonic inhibition in MGB of FXS patients could explain the increase in auditory sensitivity and be a target for therapy to reduce sensory hypersensitivity. Studies from our laboratory have revealed that neuro-active steroids (NASs) act via a metabotropic, kinase dependent mechanism to increase the phosphorylation of serine 443 in the α4 subunit to promote GABAAR insertion into the plasma membrane leading to sustained elevations in their accumulation on the cell surface and increases in the efficacy of tonic inhibition. These preliminary studies have allowed us to formulate a central hypothesis that will be tested here; Hypersensitivity to sensory stimuli in FXS is caused by reduced tonic inhibition in the central auditory system due to mis-trafficking of α4 subunits to GABAergic synapses. Exposure to neuroactive steroids will increase the trafficking of α4 subunit containing GABAARs to the membrane to boost tonic inhibition and diminish the severity of the disorder. Aim 1. Characterize the phosphorylation and sub-cellular localization of α4 subunit containing GABAARs in Fmr1 KO mice. Aim 2. Examine the electroencephalographic (EEG) activity of Fmr1 KO mice. Aim 3. Determine the efficacy of NAS treatment to reverse deficits in GABAergic inhibition and neuronal excitability. The result of this study will provide new insights into the mechanisms that regulate the efficacy of tonic inhibition and if that alterations in these contribute to the pathophysiology of FXS. Such insights may promote the development of new therapeutics to alleviate the burdens of FXS.

脆性 X 综合征 (FXS) 是遗传性智力障碍的最常见形式，也是一种主要的遗传性智力障碍。 FXS 的症状包括感觉过敏。 FXS 的原因是脆性 X 智力迟钝蛋白 (FMRP) 的缺失。 这些症状的潜在途径和机制尚不清楚。 FXS 患者和动物模型的研究表明，它们是大脑中主要的抑制性离子通道。 揭示了 GABAAR α4 亚基表达水平的改变，伴随着补品功效的降低 抑制，一种非突触类型的抑制，对于确定神经元输出的增益很重要，因此 我们的初步数据表明，在 Fmr1 KO 小鼠中，调节神经回路的兴奋性和活动。 α4 亚基磷酸化减少，导致强直电流减少，电流增加 兴奋抑制的缺陷是由于含 α4 的 GABAAR 的运输中断造成的。 FXS 患者和 Fmr1 KO 小鼠均表现出听觉处理缺陷。 他们对声音非常敏感，由内侧的听觉神经元处理。 膝状体（MGB）上升到听觉皮层时，听觉丘脑神经元的兴奋是。 由依赖于含有 α4 亚基的 GABAAR 的强直抑制控制，减少强直抑制。 FXS 患者的 MGB 可以解释听觉敏感性的增加，并成为减少听觉敏感性的治疗目标 我们实验室的研究表明，神经活性类固醇（NAS）通过 代谢型、激酶依赖性机制可增加 α4 亚基中丝氨酸 443 的磷酸化，从而 促进 GABAAR 插入质膜，导致其积累持续升高 这些初步研究使我们能够 制定将在此处进行测试的中心假设； 由于α4亚基的错误运输导致中枢听觉系统的强直性抑制减少 GABA 能突触接触神经活性类固醇会增加 α4 亚基的运输。 膜上含有 GABAAR，可增强强直抑制并减轻炎症的严重程度 紊乱。 目标 1. 表征含有 α4 亚基的磷酸化和亚细胞定位 Fmr1 KO 小鼠中的 GABAAR 目标 2. 检查 Fmr1 KO 的脑电图 (EEG) 活性。 目标 3. 确定 NAS 治疗逆转 GABA 能抑制缺陷的功效。 这项研究的结果将为调节神经兴奋性的机制提供新的见解。 强直抑制的功效以及这些变化是否有助于 FXS 的病理生理学。 这些见解可能会促进新疗法的开发，以减轻 FXS 的负担。