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，是基于明显的神经系统症状脆弱的X综合征（FXS）。然而，在FXS中改变了皮层电路开发的精度方式尚未完全阐明。我们和其他人最近的工作确定了当地电路中间神经元（INS）可能是了解FXS中皮质电路的关键。我们证明了密度，成熟度 Parvalbumin（PV）皮质INS的活性都在FMR1敲除（KO）小鼠模型中均降低 FXS。在这里，我们建议通过确定出生，迁移的方式来解决该领域的杰出问题 PV INS的连通性在FMR1 KO小鼠中被破坏，这如何导致感觉超敏反应和触觉防御。我们将使用出生日期对PV INS进行详细的分析，神经解剖学和功能研究，以定义PV INS异常整合到前馈中原发性体感皮层（S1）中的电路有助于非典型的感觉处理。在初步研究，我们证明，为了响应重复的晶须刺激，FMR1 KO小鼠显示适应不良的避免行为与缺乏层（L）2/3锥体的神经元适应性相关的行为 S1中的神经元。我们还表明，PV INS及其前体来自内侧神经节杰出（MGE）通过产后（p）6在FMR1 KO小鼠的S1中发动不良，并且增加了少数活动的活性使用兴奋性恐惧的天数将其密度显着增加了P15。现在我们将确定是否 MGE衍生的INS或更成熟的PV INS的类似早期活动操纵可以恢复 FMR1 KO小鼠中L2/3神经元和改善触觉防御性的感觉适应的丧失。我们将解决以下重要问题：1。神经发生，迁移的贡献是什么 FXS中PV INS密度降低的连通性和发育凋亡？ 2。如何衍生MGE INS和金字塔神经元在产后早期的关键时期相互作用，他们的“握手”如何 FXS有所不同吗？ 3。是PV INS或它们的前体因果关系的不良性，行为定义 FMR1 KO小鼠？机械实验设计员工细胞类型特异性遗传学，体内钙成像，化学遗传学和离体电路通道 - 偶录蛋白连接映射，其他的。这笔赠款的一个重要目标是确定针对INS是否是可行的治疗途径 FXS。因此，这种新颖的KV3.1通道的变构调节药物（负责快速尖峰） PV INS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 UCLA的Carlos Portera-Cailliau博士（Co-Pi）和西北大学的Anis承包商（Co-Pi）博士将启用一种全面的方法来理解 INS FXS的病理生理学。