Cortical Interneuron Dysfunction in Fragile X Syndrome

脆性 X 综合征中的皮质中间神经元功能障碍

基本信息

批准号：
10418431
负责人：
Anis Contractor
金额：
$ 51.27万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418431
关键词：
Acute Adaptive Behaviors Address Adult Affect Animal Model Animals Apoptosis Behavior Biological Assay Birth Brain Bromodeoxyuridine Calcium Caspase Cell Death Cell Density Cells Cessation of life Characteristics Chronic Collaborations Contractor Data Development Experimental Designs FMR1 Fragile X Syndrome Functional disorder Ganglia Genes Genetic Goals Grant Hypersensitivity Image Impairment In Vitro Individual Intellectual functioning disability Interneurons Knock-out Knockout Mice Laboratories Maps Medial Mus Neurodevelopmental Disorder Neurologic Symptoms Neurons Parvalbumins Perceptual learning Pharmaceutical Preparations Phenocopy Phenotype Pyramidal Cells Quality of life Reporting Rhodopsin Sensory Slice Somatosensory Cortex Somatostatin Symptoms Tactile Testing Therapeutic Time Universities Vibrissae Work autism spectrum disorder avoidance behavior cell type critical period density designer receptors exclusively activated by designer drugs hippocampal pyramidal neuron in vivo in vivo calcium imaging interdisciplinary approach loss of function mature animal migration mouse model nerve stem cell neurogenesis novel patch clamp postnatal response small molecule therapeutic target tool translational study two-photon

项目摘要

SUMMARY Cortical circuit dysfunction is a primary pathophysiology that underlies prominent neurological symptoms of Fragile X Syndrome (FXS). Yet the precise way in which circuit development in the cortex is altered in FXS has not been fully elucidated. Recent work by us, and others, has established that local circuit interneurons (INs) may be a key to understanding cortical circuits in FXS. We demonstrated that the density, maturity and activity of parvalbumin (PV) cortical INs are all reduced in the Fmr1 knockout (KO) mouse model of FXS. Here we propose to address outstanding questions in the field by determining how the birth, migration and connectivity of PV INs are disrupted in Fmr1 KO mice, and how this leads to sensory hypersensitivity and tactile defensiveness. We will incorporate a detailed analysis of PV INs using birth dating, neuroanatomical and functional studies to define how the abnormal integration of PV INs into feedforward circuits in the primary somatosensory cortex (S1) contributes to atypical sensory processing. In preliminary studies, we demonstrate that, in response to repetitive whisker stimulation, Fmr1 KO mice display maladaptive avoidance behaviors that correlate with a lack of neuronal adaptation of layer (L) 2/3 pyramidal neurons in S1. We also show that PV INs and their precursors from the medial ganglionic eminence (MGE) are hypoactive in S1 of Fmr1 KO mice by postnatal day (P) 6, and that increasing their activity for a few days using excitatory DREADDs significantly increases their density by P15. We will now determine whether similar early activity manipulations of MGE-derived INs, or later on in more mature PV INs, can restore the loss of sensory adaptation of L2/3 neurons and ameliorate tactile defensiveness in Fmr1 KO mice. We will address the following important questions: 1. What are the contributions of neurogenesis, migration, connectivity and developmental apoptosis to the reduced density of PV INs in FXS? 2. How do MGE-derived INs and pyramidal neurons interact during the early postnatal critical period and how is their ‘handshake’ different in FXS? 3. Is the hypoactivity of PV INs or their precursors causal to the circuit and behavior deficits of Fmr1 KO mice? The mechanistic experimental design employs cell type-specific intersectional genetics, in vivo calcium imaging, chemogenetics, and ex vivo circuit channel-rhodopsin connectivity mapping, among others. An important goal of this grant is to identify whether targeting INs is a viable path for therapeutics in FXS. As such a novel class of allosteric modulating drugs of Kv3.1 channels (responsible for fast-spiking characteristics of PV INs) will be tested in Fmr1 KO mice. Overall, the collaboration between the laboratories of Dr. Carlos Portera-Cailliau (co-PI, PL) at UCLA and Dr. Anis Contractor (co-PI) at Northwestern University will enable a comprehensive approach to understanding the developmental and functional contributions of INs to the pathophysiology of FXS.

概括皮质回路功能障碍是一种主要的病理生理学，是以下疾病突出神经系统症状的基础：脆性 X 综合征 (FXS) 然而，FXS 改变了皮质回路发育的精确方式。我们和其他人最近的工作尚未完全阐明，已经确定局部电路中间神经元。（IN）可能是理解 FXS 皮质回路的关键，我们证明了其密度、成熟度。 Fmr1 敲除 (KO) 小鼠模型中小清蛋白 (PV) 皮质 IN 的活性均降低在这里，我们建议通过确定如何出生、迁移来解决该领域的突出问题。 Fmr1 KO 小鼠中 PV IN 的连接被破坏，以及这如何导致感觉超敏反应我们将使用出生日期对 PV IN 进行详细分析，神经解剖学和功能研究，以确定 PV IN 的异常整合如何进入前馈初级体感皮层 (S1) 中的回路有助于初步的非典型感觉处理。研究中，我们证明，响应重复的胡须刺激，Fmr1 KO 小鼠表现出与 (L) 2/3 锥体层神经适应缺乏相关的适应不良回避行为我们还展示了来自内侧神经节隆起 (MGE) 的 PV IN 及其前体。 Fmr1 KO 小鼠的 S1 在出生后第 6 天 (P) 时活性降低，并且少数小鼠的活性增加使用兴奋性 DREADD 的天数显着增加其密度 P15。对 MGE 衍生的 IN 进行类似的早期活性操作，或者稍后在更成熟的 PV IN 中进行类似的活性操作，可以恢复 Fmr1 KO 小鼠 L2/3 神经元感觉适应丧失并改善触觉防御能力。解决以下重要问题： 1. 神经发生、迁移、连接性和发育凋亡对 FXS 中 PV IN 密度降低的影响 2. MGE 是如何衍生的？ INs和锥体神经元在产后早期关键期相互作用以及它们如何“握手” FXS 中有何不同？ 3. PV IN 或其前兆的低活性是否会导致电路和行为缺陷 Fmr1 KO 小鼠的机制实验设计采用细胞类型特异性交叉遗传学，体内钙成像、化学遗传学和离体电路通道-视紫红质连接图谱等此项资助的一个重要目标是确定靶向 IN 是否是治疗的可行途径。 FXS 作为 Kv3.1 通道的一类新型变构调节药物（负责快速尖峰） PV IN 的特征）将在 Fmr1 KO 小鼠中进行测试总体而言，实验室之间的合作。加州大学洛杉矶分校 Carlos Portera-Cailliau 博士（联合 PI、PL）和西北大学 Anis Contractor 博士（联合 PI）将能够采用全面的方法来理解发育和功能的贡献 FXS 病理生理学的 INs。