Department of Neuroscience, Ohio State University, Graves Hall, Rm 4118, 333 W. 10th Ave, Columbus, OH 43210, USA.
Brain Struct Funct. 2013 May;218(3):817-31. doi: 10.1007/s00429-012-0431-4. Epub 2012 Jun 16.
Within the central nervous system, microRNAs have emerged as important effectors of an array of developmental, physiological, and cognitive processes. Along these lines, the CREB-regulated microRNA miR-132 has been shown to influence neuronal maturation via its effects on dendritic arborization and spinogenesis. In the mature nervous system, dysregulation of miR-132 has been suggested to play a role in a number of neurocognitive disorders characterized by aberrant synaptogenesis. However, little is known about the inducible expression and function of miR-132 under normal physiological conditions in vivo. Here, we begin to explore this question within the context of learning and memory. Using in situ hybridization, we show that the presentation of a spatial memory task induced a significant ~1.5-fold increase in miR-132 expression within the CA1, CA3, and GCL excitatory cell layers of the hippocampus. To examine the role of miR-132 in hippocampal-dependent learning and memory, we employ a doxycycline-regulated miR-132 transgenic mouse strain to drive varying levels of transgenic miR-132 expression. These studies revealed that relatively low levels of transgenic miR-132 expression, paralleling the level of expression in the hippocampus following a spatial memory task, significantly enhanced cognitive capacity. In contrast, higher (supra-physiological) levels of miR-132 (>3-fold) inhibited learning. Interestingly, both the impaired cognition and elevated levels of dendritic spines resulting from supra-physiological levels of transgenic miR-132 were reversed by doxycycline suppression of transgene expression. Together, these data indicate that miR-132 functions as a key activity-dependent regulator of cognition, and that miR-132 expression must be maintained within a limited range to ensure normal learning and memory formation.
在中枢神经系统中，microRNAs 已成为一系列发育、生理和认知过程的重要效应因子。沿着这条线，CREB 调节的 microRNA miR-132 已被证明通过其对树突分支和棘突生成的影响来影响神经元成熟。在成熟的神经系统中，miR-132 的失调被认为在许多以异常突触发生为特征的神经认知障碍中发挥作用。然而，关于 miR-132 在体内正常生理条件下的诱导表达和功能知之甚少。在这里，我们开始在学习和记忆的背景下探索这个问题。通过原位杂交，我们显示在空间记忆任务中呈现会导致海马体 CA1、CA3 和 GCL 兴奋性细胞层中的 miR-132 表达显著增加约 1.5 倍。为了研究 miR-132 在海马体依赖的学习和记忆中的作用，我们使用强力霉素调节的 miR-132 转基因小鼠品系来驱动不同水平的转基因 miR-132 表达。这些研究表明，相对低水平的转基因 miR-132 表达，与空间记忆任务后海马体中的表达水平平行，显著增强了认知能力。相比之下，更高（超生理）水平的 miR-132（>3 倍）抑制了学习。有趣的是，由于超生理水平的转基因 miR-132 导致的认知障碍和树突棘数量增加都可以通过强力霉素抑制转基因表达来逆转。总之，这些数据表明 miR-132 是认知的关键活性依赖性调节因子，并且 miR-132 的表达必须保持在有限的范围内，以确保正常的学习和记忆形成。
