SYNAPTOGENESIS IN THE CEREBRAL CORTEX

描述（来自申请人摘要的逐字）：长期目标是 了解细胞和分子机制连接感官体验 在生命早期至躯体感觉神经兴奋性突触成熟期间， 皮层皮质突触的成熟可以通过生物病理学检测， 重复突触前动作电位引起EPSP抑制的转换 （不成熟）到EPSP易化（更成熟）。一般工作假设 突触后结构的分子组成与 并赋予突触前轴突成熟的程度。我们将测试 这一假设通过结合多个，突触 大鼠体感皮层脑片内神经元的电子连接 显微镜（EM）免疫细胞化学（ICC）分析记录的神经元， 确定是否：（1）更成熟，促进突触表现出NMDA 受体（NMDAR）亚单位-NR 1，NR 2A，以及AMPA受体和神经元 一氧化氮合酶（nNOS）在突触后密度;（2）未成熟的， 抑制性突触的特征是“先锋”NMDAR， （3）神经元nNOS通过PSD-95沿着被激活; 这些先驱NMDAR调节细胞质NMDAR和AMPA的募集 受体亚单位对新生突触后位点的作用;（4）药物阻断 将阻止NMDAR和AMPA的NR 1/NR 2A异聚体的插入 受体，也延迟或取消突触的开关， 到促进表型。青木和雷耶斯的作品表明， 突触成熟度在单层内变化很大， 神经元因此，单个突触的EM、ICC和生物物理学分析的组合 单个突触后密度应该特别有助于阐明 超微结构、分子组成和 早期形成的兴奋性突触的生理特性 出生后的生活在躯体感觉皮层，并决定终身的能力， 皮质神经功能需要从这种研究中获得的知识， 设计分子补救措施，以治疗因感觉剥夺而造成的缺陷， 早年生活

DESCRIPTION(Verbatim from the Applicant's Abstract): The long-term goal is to understand the cellular and molecular mechanisms linking sensory experience during early life to maturation of excitatory synapses in the somatosensory 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 rat somatosensory 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, as well as the AMPA receptors and neuronal nitric oxide synthase (nNOS) at postsynaptic densities; (2) the immature, depressing synapses are characterized by 'pioneer' NMDARs that arrive to the plasma membrane first, along with neuronal nNOS via PSD-95; (3) activation of these pioneer NMDARs regulate recruitment of cytoplasmic NMDAR and AMPA receptor subunits to nascent postsynaptic sites; (4) pharmacological blockage of NMDAR will prevent the insertion of NR1/NR2A heteromers of NMDAR and AMPA receptors 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 somatosensory 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.