Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
J Neurosci. 2013 Jul 31;33(31):12825-34. doi: 10.1523/JNEUROSCI.0783-13.2013.
Notch is a cell surface receptor that is known to regulate developmental processes by establishing physical contact between neighboring cells. Many recent studies show that it also plays an important role in the formation of long-term memory (LTM) in adults, implying that memory formation requires regulation at the level of cell-cell contacts among brain cells. Neither the target of Notch activity in LTM formation nor the underlying mechanism of regulation is known. We report here results of our studies in adult Drosophila melanogaster showing that Notch regulates dCrebB-17A, the CREB protein. CREB is a transcriptional factor that is pivotal for intrinsic and synaptic plasticity involved in LTM formation. Notch in conjunction with PKC activity upregulates the level of a hyperphosphorylated form of CREB (hyper-PO4 CREB) and triggers its ultradian oscillation, both of which are linked to LTM formation. One of the sites that is phosphorylated in hyper-PO4 CREB is serine 231, which is the functional equivalent of mammalian CREB serine 133, the phosphorylation of which is an important regulator of CREB functions. Our data suggest the model that Notch and PKC activities generate a cyclical accumulation of cytoplasmic hyper-PO4 CREB that is a precursor for generating the nuclear CREB isoforms. Cyclical accumulation of CREB might be important for repetitive aspects of LTM formation, such as memory consolidation. Because Notch, PKC, and CREB have been implicated in many neurodegenerative diseases (e.g., Alzheimer's disease), our data might also shed some light on memory loss and dementia.
Notch 是一种细胞表面受体，已知通过在相邻细胞之间建立物理接触来调节发育过程。许多最近的研究表明，它在成年人大脑长期记忆 (LTM) 的形成中也起着重要作用，这意味着记忆形成需要在脑细胞之间的细胞-细胞接触水平进行调节。Notch 在 LTM 形成中的作用靶标或调节的潜在机制尚不清楚。我们在此报告我们在成年果蝇中的研究结果，表明 Notch 调节 CREB 蛋白 dCrebB-17A。CREB 是一种转录因子，对于涉及 LTM 形成的内在和突触可塑性至关重要。Notch 与 PKC 活性一起上调高度磷酸化形式的 CREB（hyper-PO4 CREB）的水平，并触发其超昼夜振荡，两者都与 LTM 形成有关。hyper-PO4 CREB 中磷酸化的一个位点是丝氨酸 231，它是哺乳动物 CREB 丝氨酸 133 的功能等效物，其磷酸化是 CREB 功能的重要调节剂。我们的数据表明，Notch 和 PKC 活性产生细胞质 hyper-PO4 CREB 的周期性积累的模型，hyper-PO4 CREB 是产生核 CREB 同工型的前体。CREB 的周期性积累可能对 LTM 形成的重复方面很重要，例如记忆巩固。由于 Notch、PKC 和 CREB 已被牵连到许多神经退行性疾病（例如阿尔茨海默病）中，我们的数据也可能为记忆丧失和痴呆症提供一些线索。
