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

• 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
• 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

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.

摘要 皮质环路功能障碍是一种主要的病理生理学机制，它是脑血管病显著神经症状的基础。 脆性X综合征(FXS)。然而，在FXS中，大脑皮质回路发育发生变化的确切方式 还没有完全阐明。我们和其他人最近的研究表明，局部环路中间神经元 (INS)可能是了解FXS皮质环路的关键。我们证明了密度、成熟度 在Fmr1基因敲除(KO)小鼠模型中，小白蛋白(PV)皮质INS活性均降低。 FXS。在这里，我们建议通过确定出生、迁徙 在Fmr1KO小鼠中，PV INS的连接性被破坏，以及这是如何导致感觉过敏的 以及触觉的防御性。我们将使用出生日期对PV INS进行详细分析， 神经解剖学和功能研究确定PV INS如何异常整合到前馈 初级躯体感觉皮层(S1)中的回路参与了非典型感觉加工。在预赛中 研究表明，对重复的胡须刺激，Fmr1 KO小鼠表现出 与缺乏神经元适应相关的不良回避行为(L)2/3锥体 S1中的神经元。我们还发现PV INS及其前体来自内侧神经节隆起(MGE)。 在出生后第6天，Fmr1KO小鼠的S1中活性降低，并在几天内增加它们的活性 使用兴奋性DREADD的天数显著增加了P15的密度。我们现在将确定是否 类似的MGE衍生INS的早期活动操作，或稍后在更成熟的PV INS中，可以恢复 Fmr1KO小鼠L2/3神经元感觉适应性丧失和触觉防御能力改善。我们会 解决以下重要问题：1.神经发生、迁移、 FXS中PV INS密度降低与连通性和发育中的细胞凋亡？2.MGE是如何派生的 INS和锥体神经元在出生后早期关键期的相互作用以及它们是如何“握手”的 在FXS中不同？3.PV Ins或其前体活动不足是电路和行为缺陷的原因吗？ Fmr1 KO小鼠？机械实验设计采用了特定细胞类型的交叉遗传学， 体内钙成像、化学遗传学和体外电路通道-视紫红质连接图谱，其中 其他。这笔赠款的一个重要目标是确定靶向INS是否是一种可行的治疗方法 FXS。作为这样一类新的KV3.1通道的变构调节药物(负责快速放电 将在Fmr1 KO小鼠身上测试PV INS的特征。总体而言，实验室之间的合作 加州大学洛杉矶分校的Carlos Portera-Cailliau博士(联名PI，PL)和西北大学的Anis Contracant博士(联名PI) 将使我们能够以一种全面的方法来理解 INS参与FXS的病理生理学。