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: 9896570
• 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/9896570
• 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; Psychotic Disorders; Recovery; Research; Resolution; Role; Seizures; Sensory; Shapes; Signal Transduction; Somatosensory Cortex; Synapses; Syndrome; Testing; Time; Work; analog; 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.

痂状体(CC)是连接同位区的最大连合投射。 哺乳动物的半球。CC的连通性对于协调运动-感觉功能和 许多更高级的认知过程。CC也是理解电路的有价值的模型系统 发展以及潜在的电路形式和功能障碍的可能机制，如 精神病、自闭症和癫痫。我们对NMDA受体(大脑皮层的主要兴奋性神经递质受体)在大脑皮层回路发育和维持中的作用产生了兴趣。NMDAR位于突触，在许多情况下对电路可塑性至关重要，也已知在发育过程中与引导信号相互作用，如Eph受体(EphR)。此外，NMDAR功能障碍由以下原因引起 最近，抗NMDAR抗体作为精神病的模型而获得了突出的地位。抗-HBs阳性患者 NMDAR抗体脑炎表现为精神错乱、异常运动和癫痫。临床部 这种综合征的特点，包括亚急性起病和治疗后恢复缓慢表明 电路完整性水平上的功能中断，而不是简单的药物拮抗。 我们正在研究NMDAR在CC躯体感觉投射发展中的作用。我们发现 Emx1cre/+；NR1fl/fl小鼠，在E10.5之后，在皮质中缺乏NMDAR，在 初级躯体感觉皮质(S1)，这与EphB2表达的变化有关。我们的 分析表明，初始神经支配和随后的改进都存在缺陷。此外，脑室内注射 抗NMDAR抗体与病原性患者抗体类似，会导致S1的神经支配类似的缺陷。 我们认为，NMDAR的功能对于同伦的膝盖骨投射是必要的，即 NMDAR通过影响轴突寻径和/或轴突修剪，在形成穹隆神经回路方面具有特殊的作用 而持续的NMDAR功能对脑组织形态的维持至关重要 巡回赛。下面的目标将测试这些命题并检查潜在的分子机制。 目的：确定NMDAR在骨痂发育中的解剖和时间作用。 目的：研究NR2A和NR2B亚基在骨痂发育中的作用。 目的：研究NMDAR和EPhinB/EphB信号在骨痂发育过程中的相互作用。