Identification of a non-invasive neuroimaging biomarker of prenatal synaptic development

项目总结和摘要 妊娠期发育过程中发生的最深刻的变化之一是， 神经元之间的联系发生在子宫内的突触发生或突触的形成对于 随后的神经发育，以及几种精神和发育障碍被认为是 产前突触发生改变的结果。直到最近，突触量化还需要后- 因此，直接证据表明，产前突触中断与产后神经和行为 发展受到限制。我们最近开发了一种新的正电子发射断层扫描（PET） 靶向突触囊泡糖蛋白2A（SV 2A）的放射性配体（[11 C]UCB-J），SV 2A是一种在几乎所有神经元中表达的蛋白质。 突触囊泡，并已证明[11 C]UCB-J能够检测人类 疾病，如阿尔茨海默病。我们已经进行了一项初步研究，使用[11 C]UCB-J来量化突触 在非人类灵长类动物的产前和产后发育过程中， [11 C]UCB-J结合的变化与突触发生的死后测量平行。因此，我们认为， 用[11 C]UCB-J纵向表征突触密度有可能提供前所未有的 深入了解精神疾病背后的发展机制。本提案将使用[11 C]UCB-J， 在非人类灵长类动物的整个妊娠期和出生后的前九个月内量化突触， 确定产前突触发育和出生后发育之间的预测关系， 大脑和认知在第一个目标中，我们将在妊娠期间（受孕后第120天和第150天）定量SV 2A。 和出生后（出生后第15、30、60、120和240天），以确定SV 2A的发育轨迹 与奖励学习、工作记忆和反应抑制的变化相关，这些变化是认知的 已知在精神疾病中改变的领域。第二个目标将决定 产前SV 2A密度和磁共振（MR）测量，以确定推定的MR生物标志物， 产前突触密度，可以作为一个非侵入性的诊断工具，用于人类婴儿。措施 将在同一婴儿中纵向评估脑形态测量学、髓鞘形成和功能连接 出生后（出生后第30、60、120和240天）用于目标1的非人灵长类动物，与突触相关 和认知发展轨迹。这些研究的正常发展在非- 人类灵长类动物将为未来在精神疾病动物模型中检查SV 2A的研究提供初步数据。 疾病，并最终导致产前突触的非侵入性MR成像生物标志物的鉴定。 可以在人类婴儿和儿童中安全获得的密度，并用作诊断工具。

Project summary and abstract One of the most profound changes that occurs during gestational development is the rapid increase in the connections between neurons. Synaptogenesis, or the formation of synapses, that occurs in utero is critical for subsequent neural development, and several mental and developmental disorders are believed to be the resultant of alterations in prenatal synaptogenesis. Synaptic quantification, until recently, has required post- mortem tissue, so direct evidence linking prenatal synaptic disruptions with postnatal neural and behavioral development has been limited. We have recently developed a novel positron emission tomography (PET) radioligand ([11C]UCB-J) that targets synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in almost all synaptic vesicles, and have demonstrated that [11C]UCB-J is able to detect subtle alterations in human disorders, such as Alzheimer’s disease. We have conducted a pilot study using [11C]UCB-J to quantify synaptic development throughout prenatal and postnatal development in non-human primates and have found striking changes in [11C]UCB-J binding that parallel post-mortem measures of synaptogenesis. Therefore, longitudinally characterization of synaptic density with [11C]UCB-J has the potential to provide unprecedented insight into the developmental mechanisms that underlie mental illness. This proposal will use [11C]UCB-J to quantify synapses throughout gestation and the first nine postnatal months in non-human primates to determine the predictive relationship between prenatal synaptic development and postnatal development of the brain and cognition. In the first aim, we will quantify SV2A during gestation (post-conception days 120 and 150) and following birth (postnatal days 15, 30, 60, 120 and 240) to determine if development trajectories of SV2A co-vary with changes in reward learning, working memory and response inhibition, which are cognitive domains known to be altered in mental illness. The second aim will determine the relationship between prenatal SV2A density and magnetic resonance (MR) measures in order to identify a putative MR biomarker of prenatal synaptic density that could serve as a noninvasive diagnostic tool for use in human infants. Measures of brain morphometry, myelination and functional connectivity will be longitudinally assessed in the same infant non-human primates used in Aim 1 following birth (postnatal days 30, 60, 120 and 240) and related to synaptic and cognitive development trajectories of the same monkey. These studies of normal development in non- human primates will provide the preliminary data for future studies examining SV2A in animal models of mental illness, and ultimately lead to the identification of noninvasive MR imaging biomarker of prenatal synaptic density that can be safely acquired in human infants and children and serve as a diagnostic tool.