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.

胼胝体（CC）是连接胼胝体的同伦区域的最大连合投影。 哺乳动物的大脑半球CC的连通性对于协调运动-感觉功能至关重要， 对于许多高级认知过程来说。CC也是理解电路的一个有价值的模型系统 发展以及潜在的电路形式和功能障碍的可能机制， 精神病自闭症和癫痫我们对NMDA受体（皮层中主要的兴奋性神经递质受体）在皮层回路发育和维持中的作用产生了兴趣。NMDAR位于突触处，并且已知在许多情况下对回路可塑性至关重要，并且还已知在发育期间与引导线索（诸如Eph受体（EphR））相互作用。此外，由NMDAR引起的NMDAR功能障碍 抗NMDAR抗体作为精神病的模型近来已经获得了显著的地位。抗- NMDAR抗体脑炎表现为精神病、运动异常和癫痫发作。临床 这种综合征的特点，包括亚急性发作和治疗后恢复缓慢，表明 在回路完整性水平上的功能中断，而不是简单的药理学拮抗作用。 我们正在研究NMDAR在CC体感投射发展中的作用。我们发现 E10.5后在皮质中特异性缺乏NMDAR的Emx1cre/+; NR1fl/fl小鼠， 初级躯体感觉皮层（S1），这与EphB2表达的改变有关。我们 分析显示了初始神经支配和随后的细化两者的缺陷。此外，脑室内注射 抗NMDAR抗体与致病性患者抗体相似，在S1的神经支配中引起相似的缺陷。 我们提出，NMDAR的功能是必要的同伦胼胝体投影， NMDAR通过影响轴突寻路和/或轴突修剪在塑造胼胝体回路中具有特定的作用 持续的NMDAR功能对于发育中的大脑皮层的形态维持至关重要。 电路。下面的目标将测试这些命题，并检查潜在的分子机制。 目的1：明确NMDAR在胼胝体发育中的解剖学和时间学作用。 目的2：研究NR2A和NR2B亚基在胼胝体发育中的作用。 目的3：鉴定胼胝体发育中NMDAR和EphrinB/EphB信号传导之间的相互作用。