Chemically specified synaptogenesis in the visual cortex

视觉皮层中化学指定的突触发生

• 批准号: 6525068
• 负责人: CHIYE J AOKI
• 金额: $ 25.66万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525068
• 关键词: NMDA receptors; acetylcholine; action potentials; brain; chemical stimulation; cholinergic receptors; computer data analysis; early experience; electrodes; electron microscopy; electrophysiology; immunocytochemistry; laboratory rat; light microscopy; muscarinic receptor; neurons; newborn animals; organ culture; synaptogenesis; visual cortex; voltage /patch clamp

DESCRIPTION (adapted from applicant's abstract): The long-term goal is to understand the cellular and molecular mechanisms linking visual experience during early life to maturation of excitatory synapses in the visual cortex. The maturation of cortical synapses can be detected biophysically by a switch from EPSP depression following repetitive presynaptic action potentials (immature) to EPSP facilitation (more mature). The general working hypothesis is that the molecular composition of postsynaptic structures correlates with and confers the degree of maturity upon the presynaptic axons. We will test this hypothesis by combining patch-recording of multiple, synaptically connected neurons within neonatal rat visual cortical slices with electron microscopic (EM) - immuno- cytochemical (ICC) analysis of the recorded neurons to DETERMINE WHETHER: (1) the more mature, facilitating synapses exhibit the NMDA receptor (NMDAR) subunits - NR1, NR2A - at postsynaptic densities, as well as the muscarinic acetylcholinergic receptors (mAChR) pen-synaptically; (2) the immature, depressing synapses are characterized by pioneer NMDARs that arrive to the plasma membrane first, along with alpha7 nicotinic AChR; (3) activation of these 'pioneer' NMDARs regulate recruitment of cytoplasmic NMDAR subunits and mAChRs to nascent postsynaptic sites; (4) pharmacological blockade of NMDAR will prevent the insertion of NR1/NR2A heteromers of NMDAR and AChR and also delay or abolish the switch at synapses from the depressing to the facilitating phenotype. The works of Aoki and Reyes indicate that synapse maturity can vary widely within single layers and even within single neurons. Thus, the combined EM, ICC and biophysical analysis of single synapses and single postsynaptic densities should be particularly helpful in elucidating functional links between ultrastructure, molecular composition, and physiological properties of excitatory synapses that form during early postnatal life in the visual cortex and dictate life-long capacities of cortical neural function. The knowledge gained from such a study is required in designing molecular remedies for deficits caused by sensory deprivation during early life.

描述（改编自申请人的摘要）：长期目标是了解连接视觉体验的细胞和分子机制 在早期生命中，视觉皮层中兴奋性突触的成熟。 可以通过开关检测皮质突触的成熟 重复突触前动作电位后的EPSP抑郁症 （不成熟）到EPSP促进（更成熟）。一般工作假设 是突触后结构的分子组成与 并赋予突触前轴突上的成熟程度。我们将测试 通过结合多个，突触上的斑块录制，该假设 新生大鼠视觉皮层切片中的神经元与电子 显微镜（EM） - 记录神经元的免疫细胞化学（ICC）分析 确定：（1）越成熟，促进突触表现出 NMDA受体（NMDAR）亚基-NR1，NR2A - 在突触后密度也 作为毒蕈碱乙酰胆碱能受体（MACHR），突触； （2） 未成熟，令人沮丧的突触的特征是先驱NMDAR的来临 首先与质膜一起使用α7烟碱aChR； （3）激活 这些“先驱” NMDAR调节细胞质NMDAR亚基的募集 和马克尔到新生的突触后地点； （4）NMDAR的药理阻滞 将防止插入NMDAR和ACHR的NR1/NR2A异构体以及 延迟或废除突触的开关，从凹陷到促进 表型。 Aoki和Reyes的作品表明，突触的成熟度可能会有所不同 广泛在单层甚至单个神经元内。因此，结合了 EM，ICC和单个突触和单一突触的生物物理分析 密度应特别有助于阐明功能链接 在超微结构，分子组成和生理特性之间 在视觉皮层中产后早期生活中形成的兴奋性突触 并决定皮质神经功能的终身能力。知识 从这样的研究中获得的研究是为了设计分子疗法的 早年的感觉剥夺引起的缺陷。