Disruption of spinal circuit early development after silencing En1/Foxp2 interneurons

沉默 En1/Foxp2 中间神经元后脊髓回路早期发育中断

• 批准号: 10752857
• 负责人: FRANCISCO J ALVAREZ
• 金额: $ 43.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752857
• 关键词: Acute; Adult; Affect; Anatomy; Ataxia; Automobile Driving; Birth; Brain Stem; Cell physiology; Central Nervous System; Cerebellum; Chemical Synapse; Chlorides; Chronic; Cochlea; Coupling; Development; Electrical Synapse; Electrophysiology (science); Elements; Embryo; Embryonic Development; Environmental Risk Factor; Etiology; Extensor; FOXP2 gene; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Flexor; Functional disorder; Future; Generations; Genetic; Genetic Models; Glycine; Hippocampus; Interneurons; Intervention; Joints; Knowledge; Left; Limb structure; Literature; Maps; Modeling; Motor; Motor Activity; Motor Neurons; Motor output; Mus; Neurodevelopmental Disorder; Neurons; Newborn Infant; Participant; Pathologic; Pattern; Periodicity; Play; Preparation; Regulation; Renshaw Cell; Resources; Retina; Role; Sensory; Shapes; Spinal; Spinal Cord; Study models; Synapses; Syndrome; Testing; Tetanus Toxin; Time; Ventral Roots; Vertebral column; Viral; Visual Pathways; Work; autism spectrum disorder; axon guidance; connectome; experimental study; extracellular; forkhead protein; gamma-Aminobutyric Acid; imprint; limb movement; malformation; motor deficit; neural circuit; neural network; neurodevelopment; neuroinflammation; nicotine exposure; patch clamp; pharmacologic; pup; retinotopic; stem; synaptic inhibition; transcription factor; voltage

ABSTRACT Rhythmic spontaneous activity episodes, known as spontaneous network activity (SNA), occur throughout the central nervous system (CNS) at the time in which the first synaptic connections are established. During this time an early connectome is form and it is through later maturation and refinement of these early connections that adult synaptic circuitries with mature functionalities emerge. Therefore, the early development of this first connectivity is critical for later adult functional networks and when genetic or environmental factors disrupt SNA the resulting adult circuits are malformed and dysfunctional. For example, SNA mechanisms are disturbed in fetal alcohol spectrum disorders resulting in anomalous circuit development in the hippocampus. Similarly, many neurodevelopmental disorders like those in the autism spectrum display associated motor deficits in the newborn. SNA has been intensely studied in some CNS regions (retina, visual pathways, hippocampus) and the exact cellular interactions involved, the assembly and disassembly of the SNA network and its significance for maturation of correctly connected adult circuits are well known. Surprisingly, less is known about SNA in spinal cord motor circuits, despite this being an early model for the study of SNA mechanisms. Currently, the literature offers contradictory conclusions on the exact types of neurons involved in the SNA spinal network and the significance of SNA for spinal circuit development remains unexplored. These are critical gaps in our knowledge given the large number of motor syndromes in newborns with unknown etiology. This exploratory proposal stems from the serendipitous finding of profound ataxia and limb discoordination in mouse pups in which spinal inhibitory interneurons expressing the transcription factors engrailed 1 (En1) and forkhead box P2 (Foxp2) were chronically silenced throughout embryonic development. This suggests major dysfunction in adult spinal motor circuits controlling limbs and preliminary results suggest disruption of early SNA in the embryo. This genetic model could therefore offer a new entry point to interrogate cellular mechanisms in the network driving SNA in the spinal cord (Aim 1) and the consequences of SNA dysfunction for the later organization of key spinal motor circuits (Aim 2). For the second aim we will use as model the most basic of motor circuits composed by extensor and flexor motoneurons, Ia reciprocal inhibitory interneurons (many of which are En1-Foxp2) and Renshaw cells. This circuit displays a well-defined organization of specific connections that has been extensively studied for many years and therefore offers an unambiguous model to test the role of SNA in establishing specific connectivity. We hypothesize that its basic organization will be disrupted by anomalous early SNA given that the principal interneurons involved in the SNA network (Renshaw cells and Ia inhibitory interneurons) are also participants in this adult circuit. We hope to generate first evidence for the usefulness of this model, and this could lead to future proposals focusing on more thorough analyses of cellular mechanisms to better understand possible origins of some newborn motor syndromes.

摘要