Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies

项目摘要 大麻是怀孕期间使用最多的非法药物之一，随着合法化程度的提高，使用大麻 在怀孕期间预计会上升。临床研究表明，产前暴露大麻素(PCE)的结果 在后代中残留的认知缺陷。尽管PCE有所上升，但人们对 与PCE相关的学习和记忆障碍的综合机制途径。我们的 长期目标是了解PCE如何影响认知，而这项提议的目标是剖析 与PCE相关的记忆和突触可塑性缺陷的分子机制。我们的初步数据 PCE动物的海马区依赖记忆损害与突触相伴 以长时程增强(LTP)和长期抑郁(LTD)增强为形式的缺陷。 此外，我们还证明了聚唾液酸化NCAM(PSA-NCAM)的减少，这是 神经发生，神经元寻路，以及学习和记忆。我们之前已经确定，减少了 PSA-NCAM可通过调节GluN2B-Ras-GRF1-p38 MAPK信号通路导致LTP缺陷 改变含有GluN2A和GluN2B的NMDA受体的信号平衡。我们的初步数据包括 PCE还表明GluN2A受体的表达和信号转导减少，而GluN2B没有变化 表达，表明信号不平衡。根据我们的初步数据和公布的数据，我们假设 PSA-NCAM介导的GluN2A和GluN2B信号通路的改变是导致 PCE引起的突触可塑性和记忆缺陷的改变。这项提案的目的是剖析 PCE诱导突触可塑性和认知缺陷的分子机制。我们将使用 多学科方法，包括行为、电化学、电生理、细胞和分子 检验我们假设的方法论。我们提出了三个相互关联但顺序独立的特定 目的：(1)研究行为和突触可塑性缺陷的分子机制。 PCE，(2)研究PSA-NCAM如何通过调节NMDA改变突触传递和可塑性 PCE动物中受体介导的信号转导，以及(3)决定应用PSA的功能结果 含GluN2A和GluN2B的NMDA受体对PCE诱导的突触可塑性的模拟和调节 和记忆力减退。我们研究的数据不仅指向了一种特定的机制 PCE相关缺陷，但也将全面评估突触分子所发挥的不同作用 负责与认知密切相关的可塑性机制。

Project Abstract Cannabis is one of the most illicit drugs used during pregnancy, and with increased legalization, use during pregnancy is expected to rise. Clinical studies have shown prenatal cannabinoid exposure (PCE) results in residual cognitive deficits in offspring. Despite the rise in PCE, there is little understanding of a comprehensive mechanistic pathway responsible for learning and memory deficits associated with PCE. Our long-range goal is to understand how PCE affects cognition, and the goal of this proposal is to dissect the molecular mechanisms of memory and synaptic plasticity deficits associated with PCE. Our preliminary data demonstrate hippocampal-dependent memory impairments in PCE animals are concomitant with synaptic deficits in the form of decreased long-term potentiation (LTP) and enhanced long-term depression (LTD). Furthermore, we have demonstrated reductions in polysialylated-NCAM (PSA-NCAM), which is required for neurogenesis, neuronal pathfinding, and learning and memory. We have previously established that decreased PSA-NCAM can lead to deficits in LTP by modulating GluN2B-Ras-GRF1-p38 MAPK signaling pathway and altering the signaling balance of GluN2A- and GluN2B- containing NMDA receptors. Our preliminary data with PCE also indicates a decrease in GluN2A receptor expression and signaling with no change in GluN2B expression, indicating an imbalance in signaling. Based on our preliminary and published data, we hypothesize that PSA-NCAM mediated alterations in GluN2A- and GluN2B- signaling pathways are responsible for the altered synaptic plasticity and memory deficits resulting from PCE. The objective of this proposal is to dissect the molecular mechanisms by which PCE induces synaptic plasticity and cognitive deficits. We will use a multidisciplinary approach including behavioral, electrochemical, electrophysiological, cellular and molecular methodologies to test our hypotheses. We propose three interrelated but sequentially independent specific aims: (1) Investigate the molecular mechanisms of behavioral and synaptic plasticity deficits resulting from PCE, (2) Investigate how PSA-NCAM modifies synaptic transmission and plasticity by regulating NMDA receptor-mediated signaling in PCE animals, and (3) Determine the functional outcomes of application of a PSA mimetic & modulation of GluN2A- and GluN2B- containing NMDA receptors on PCE-induced synaptic plasticity and memory deficits. The data from our study not only points toward a specific mechanism responsible for PCE-related deficits but will also comprehensively assess the different roles played by synaptic molecules responsible for plasticity mechanisms closely associated with cognition.