The role of mammalian CAMTA proteins in transcriptional control of neuronal morphology and long-term memory

哺乳动物 CAMTA 蛋白在神经元形态和长期记忆转录控制中的作用

• 批准号: 244445106
• 负责人: Professor Dr. Hilmar Bading
• 金额: --
• 依托单位: Anatomie I - Klinische Neuroanatomie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/244445106?language=en
• 关键词: role; mammalian; CAMTA; proteins; transcriptional

The formation of long-term memories requires long-lasting structural and functional adaptations of neurons. To instruct these adaptations, synaptic activity initiates calcium-dependent signaling cascades that lead to changes in neuronal gene expression. This synapse-to-nucleus communication involves the activation of calcium/calmodulin-dependent transcriptional regulators that include CREB, CBP, MeCP2, and MEF2. Recently a novel family of transcriptional regulators, the so-called calmodulin-binding transcription activator (CAMTA) proteins, were identified. The two mammalian CAMTA family members, CAMTA1 and CAMTA2, are highly expressed in the mouse and human brain. As calmodulin-dependent transcriptional regulators, they might be involved in synaptic activity-dependent gene expression that underlies memory formation. In line with this notion, genetic studies reported an association between CAMTA1 gene polymorphisms and cognitive performance in humans. Our recent unpublished experiments revealed that shRNA mediated knock-down of CAMTAs in the hippocampus of adult mice causes impaired long-term memory performance. In addition, we found that CAMTA knock-down in cultured mouse hippocampal neurons causes impaired dendrite growth. Dendrites are the major site of synaptic input and signal integration. Their morphology thus has a major influence on the functional properties of neurons and impacts on cognitive function. Based on our unpublished findings we thus suggest that CAMTA proteins mediate the formation of long-term memories via transcriptional control of neuronal morphology. In this proposal we will use loss-of-function and gain-of-function approaches in mouse hippocampal neurons in vitro and in the mouse hippocampus in vivo to study the role of mammalian CAMTA proteins in dendrite and dendritic spine morphogenesis and in the formation of long-term memories. In addition, we will use unbiased genomic and bioinformatics approaches to identify CAMTA target genes in neurons that mediate the morphological and cognitive CAMTA loss-of-function phenotypes. Finally, we will investigate the signaling mechanisms that link synaptic activity to CAMTA transcriptional activity.

长期记忆的形成需要神经元持久的结构和功能适应。为了指导这些适应，突触活动启动钙依赖性信号级联，导致神经元基因表达的变化。这种突触到细胞核的通讯涉及钙/钙调蛋白依赖性转录调节因子的激活，包括CREB、CBP、MeCP 2和MEF 2。最近，一个新的家族的转录调节因子，所谓的钙调素结合转录激活因子（CAMTA）蛋白，被确定。两个哺乳动物CAMTA家族成员CAMTA 1和CAMTA 2在小鼠和人脑中高度表达。作为钙调素依赖的转录调节因子，它们可能参与记忆形成的突触活性依赖的基因表达。根据这一观点，遗传学研究报告了CAMTA 1基因多态性与人类认知能力之间的关联。我们最近未发表的实验表明，shRNA介导的成年小鼠海马CAMTA的敲低导致长期记忆能力受损。此外，我们发现在培养的小鼠海马神经元中，CAMTA敲低导致树突生长受损。树突是突触输入和信号整合的主要场所。因此，它们的形态对神经元的功能特性和认知功能有重大影响。基于我们未发表的研究结果，我们认为CAMTA蛋白通过转录控制神经元形态来介导长期记忆的形成。在这个建议中，我们将使用功能丧失和功能获得的方法在小鼠海马神经元在体外和在小鼠海马在体内研究哺乳动物CAMTA蛋白在树突和树突棘形态发生和长期记忆的形成中的作用。此外，我们将使用无偏的基因组和生物信息学方法来确定介导形态和认知CAMTA功能丧失表型的神经元中的CAMTA靶基因。最后，我们将研究连接突触活动和CAMTA转录活性的信号机制。