White mater neurons & nitric oxide in neonatal neocortex

白质神经元

• 批准号: 6491083
• 负责人: MICHAEL J FRIEDLANDER
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6491083
• 关键词: brain mapping; developmental neurobiology; glutamates; laboratory rat; neocortex; neural degeneration; neural transmission; nitric oxide; synapses

Substantial human brain development, particularly synaptic reorganization of the cerebral cortex, occurs postnatally. During the early postnatal period, normal cortical development is susceptible to disruption. Causes include primary insults (seizures, infection, injury), delayed effects of earlier perinatal damage (hypoxia/ischemia, fetal alcohol exposure, infections, e.g. AIDS), and genetically linked diseases (Down's syndrome, PKU, fragile X). These processes can lead to mental retardation and are associated with abnormal cortical synaptic architecture Thus, a first understanding of the cellular and molecular mechanisms that mediate development and refinement of cortical synapses is essential The development and modifiability of glutamate-mediated synaptic transmission in the cortex is a particularly critical process as these synapses are sensitive to structural and functional modification by early experience and they can contribute to neurotoxicity from over-activation. Cortical white matter (WM) neurons develop particularly early and they can contribute to neurotoxicity from over-activation. Cortical white matter (WM) neurons develop particularly early and play an important role in establishment of initial glutamatergic synaptic linkages. Until recently, it was assumed that during normal development, most of these WM neurons die. However, we now know that a substantial portion survives and innervates the overlying cortex throughout development. Moreover, many of the neurons express the enzyme for synthesizing nitric oxide (NO) which has been implicated in glutamate release, neurodevelopment, synaptic plasticity, and neurodegeneration. However, we know little about the functional properties or synaptic interactions of these surviving WM neurons or the role of NO in modulating glutamatergic synapses during development. Thus, we propose to elucidate the functional properties, the innervation pattern, the synaptic interactions of WOM neurons, and their ability to gate the throughput of glutamatergic synapses in the overlying neonatal cortex. We will also elucidate the developmental regulation of the signaling pathway where NO is produced and acts to modulate glutamate.

人类大脑的实质性发育，特别是大脑皮层的突触重组，发生在出生后。在出生后早期，正常的皮质发育容易受到干扰。原因包括原发性损伤（癫痫发作、感染、损伤）、早期围产期损伤的延迟影响（缺氧/缺血、胎儿酒精暴露、感染，如艾滋病）和遗传相关疾病（唐氏综合征、PKU、脆性X染色体）。这些过程可能导致智力迟钝，并与皮层突触结构异常有关，皮层中谷氨酸介导的突触传递的发育和可修改性是一个特别关键的过程，因为这些突触对早期经历的结构和功能修改很敏感，并且它们可能导致过度激活的神经毒性。皮层白质（WM）神经元发育特别早，它们可能因过度激活而导致神经毒性。皮层白质（WM）神经元发育特别早，在谷氨酸能突触连接的建立中起重要作用。直到最近，人们还认为在正常发育过程中，大多数WM神经元都会死亡。然而，我们现在知道，相当一部分存活下来，并在整个发育过程中支配其上的皮层。此外，许多神经元表达合成一氧化氮（NO）的酶，一氧化氮与谷氨酸释放、神经发育、突触可塑性和神经变性有关。然而，我们对这些存活的WM神经元的功能特性或突触相互作用以及NO在发育过程中调节谷氨酸能突触中的作用知之甚少。因此，我们建议阐明WOM神经元的功能特性、神经支配模式、突触相互作用，以及它们在新生儿皮层上控制谷氨酸突触通量的能力。我们还将阐明NO产生和调节谷氨酸的信号通路的发育调控。