NMDA receptors and callosal circuitry: development and molecular mechanisms

NMDA 受体和胼胝体回路：发育和分子机制

• 批准号: 10393520
• 负责人: SAMUEL JEREMY PLEASURE
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393520
• 关键词: Address; Adult; Affect; Aftercare; Anatomy; Antibodies; Area; Autoimmune encephalitis; Axon; Biological Models; Blocking Antibodies; Cells; Cerebral cortex; Clinical; Contralateral; Corpus Callosum; Cues; Data; Defect; Development; Disease; Dyskinetic syndrome; Electroporation; Encephalitis; Eph Family Receptors; EphB2 Receptor; Ephrins; Epilepsy; Functional disorder; Future; Genetic study; Injections; Intraventricular Injections; Label; Maintenance; Mammals; Mediating; Modeling; Molecular; Morphology; Motor; Mus; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; NR1 gene; Neurons; Neurotransmitter Receptor; Pathogenicity; Patients; Pattern; Pharmacology; Phenotype; Presynaptic Terminals; Process; Psychoses; Recovery; Research; Resolution; Role; Seizures; Sensory; Shapes; Signal Transduction; Somatosensory Cortex; Synapses; Syndrome; Testing; Time; Work; analog; antagonist; autism spectrum disorder; axon guidance; axonal pathfinding; cognitive process; conditional mutant; experimental study; in utero; insight; interest; mutant; nerve supply; neural circuit; novel; receptor; repaired; somatosensory; supernova

The corpus callosum (CC) is the largest commissural projection connecting homotopic regions of the hemispheres in mammals. The connectivity of the CC is essential for coordinated motor-sensory function and for many higher cognitive processes. The CC is also a valuable model system for understanding circuit development as well as possible mechanisms underlying disorders of circuit form and function such as psychosis, autism and epilepsy. We have become interested in the role of NMDA receptors (the chief excitatory neurotransmitter receptor in the cortex) in cortical circuit development and maintenance. NMDAR are located at synapses and are known to be critical for circuit plasticity in many contexts and are also known to interact with guidance cues, such as the Eph Receptors (EphR) during development. Also, dysfunction of NMDAR caused by anti-NMDAR antibodies has achieved recent prominence as a model for psychosis. Patients with anti- NMDAR antibody encephalitis present with psychosis, abnormal movements and seizures. The clinical features of this syndrome, including the subacute onset and slow recovery after treatment suggest functional disruption at the level of circuit integrity rather than simple pharmacologic antagonism. We are examining the role of NMDAR in development of somatosensory projections of the CC. We find that Emx1cre/+; NR1fl/fl mice, lacking NMDAR specifically in the cortex after E10.5, have callosal defects in primary somatosensory cortex (S1) and that this is associated with alterations in EphB2 expression. Our analysis shows defects of both initial innervation and subsequent refinement. Also, intraventricular injections of anti-NMDAR antibodies, similar to pathogenic patient antibodies, cause similar defects in the innervation of S1. We propose, that the function of the NMDAR is necessary for homotopic callosal projections, that NMDAR have specific roles in shaping the callosal circuitry by affecting axon pathfinding and/or axon pruning in the developing cortex and that continued NMDAR function is critical for morphologic maintenance of the circuit. The aims below will test these propositions and examine potential molecular mechanisms. Aim1: Determine the anatomic and temporal roles of NMDAR in callosal development. Aim2: Characterize the role of NR2A and NR2B subunits in callosal development. Aim3: Identify interactions between NMDAR and EphrinB/EphB signaling in callosal development.

call体（CC）是连接同型区域的最大的连锁投影 哺乳动物的半球。 CC的连通性对于协调的电机感官函数至关重要 对于许多更高的认知过程。 CC也是理解电路的宝贵模型系统 开发以及电路形式和功能疾病的潜在机制，例如 精神病，自闭症和癫痫。我们已经对NMDA受体（皮质中的主要兴奋性神经递质受体）在皮质回路发育和维持中的作用感兴趣。 NMDAR位于突触，在许多情况下对电路可塑性至关重要，并且也已知与引导线索相互作用，例如在开发过程中EPH受体（EPHR）。此外，NMDAR功能障碍是由 抗NMDAR抗体已成为精神病模型的最新知名度。抗抗患者 NMDAR抗体脑炎患有精神病，异常运动和癫痫发作。临床 该综合征的特征，包括亚急性发作和治疗后缓慢的恢复表明 电路完整性水平而不是简单的药物拮抗作用的功能破坏。 我们正在研究NMDAR在CC体感觉投影发展中的作用。我们发现 那个emx1cre/+; NR1FL/FL小鼠在E10.5之后的皮质中缺少NMDAR 原代体感皮质（S1），这与EPHB2表达的改变有关。我们的 分析显示了初始神经和随后的细化的缺陷。同样，脑室室注射 抗NMDAR抗体类似于致病患者抗体，在S1神经支配中会产生相似的缺陷。 我们建议，NMDAR的功能对于同型callosol预测是必要的， NMDAR通过影响轴突路径和/或轴突修剪来塑造Callosal电路的特定作用 在发育中的皮层中，持续的NMDAR功能对于形态学维持至关重要 电路。下面的目的将测试这些命题并检查潜在的分子机制。 AIM1：确定NMDAR在Callosal开发中的解剖和时间角色。 AIM2：表征NR2A和NR2B亚基在Callosal开发中的作用。 AIM3：确定Callosal开发中NMDAR和Ephrinb/Ephb信号传导之间的相互作用。