Deciphering the molecular mechanisms controlling maturation of adult-generated hippocampal neurons

成年海马神经发生，即，海马齿状颗粒（DG）神经元的终身生成对于海马依赖性信息处理至关重要。目前的数据表明，成年海马神经发生失调参与了衰老和神经精神和退行性疾病的认知障碍的病理生理学。成年海马神经发生的调控机制还不完全清楚。该项目的总体目标是破译控制成年出生的DG神经元的功能成熟和整合的分子机制。我们最近的研究结果表明，Wnt/β-catenin通路的重新激活调节成年出生的DG神经元的成熟和突触整合。本项目旨在确定控制Wnt/β-catenin通路的重新激活和成年出生的DG神经元成熟的机制。在初步研究中，我们发现有效的Wnt/β-连环蛋白通路调节剂RSPO 2沿着苔藓纤维束（即DG神经元的轴突投射）表达。此外，我们发现了ZNRF 3（RSPO 2信号传导的靶点）在发育中的成年神经元中表达的证据。本项目研究RSPO 2/ZNRF 3通路控制成年DG神经元中Wnt/β-catenin通路的重新激活，从而调节其成熟和突触整合的假设。为了研究这一假设，我们将使用小鼠转基因和病毒介导的基因转移，以诱导RSPO 2和ZNRF 3的增益和功能丧失在体内成熟的成年出生的神经元。对i）阶段特异性神经元标志物表达，ii）轴突、树突和突触区室的形态，以及iii）电生理学特性的综合比较分析将提供对RSPO 2/ZNRF 3通路对神经元成熟和整合的功能的深入了解。此外，我们还将通过转录组学分析来确定RSPO 2/ZNRF 3下游成年DG神经元功能成熟和整合的候选靶点和调控通路。精确调控成年DG神经元的成熟对于海马信息处理具有重要意义。我们希望这个项目将揭示新的机制的原则，控制成熟的成年出生的海马神经元，从而进一步了解海马可塑性的调节。

Adult hippocampal neurogenesis, i.e., the life-long generation of hippocampal dentate granule (DG) neurons, is crucial for hippocampus-dependent information processing. Current data suggest that dysregulation of adult hippocampal neurogenesis is involved in the pathophysiology of cognitive impairment in ageing and in neuropsychiatric and -degenerative disorders. The regulatory mechanisms underlying adult hippocampal neurogenesis are not fully understood. The overall goal of this project is to decipher the molecular mechanisms controlling the functional maturation and integration of adult-born DG neurons. Our recent results show that re-activation of the Wnt/beta-catenin pathway regulates the maturation and synaptic integration of adult-born DG neurons. This project aims to identify the mechanisms that control the re-activation of the Wnt/beta-catenin pathway and maturation of adult-born DG neurons. In preliminary studies we found expression of the potent Wnt/beta-catenin pathway modulator RSPO2 along the mossy fiber tract (i.e. the axonal projections of DG neurons). Moreover, we found evidence for the expression of ZNRF3, the target of RSPO2 signaling, in developing adult-born neurons. This project investigates the hypothesis that the RSPO2/ZNRF3 pathway controls the re-activation of the Wnt/beta-catenin pathway in adult-born DG neurons thereby regulating their maturation and synaptic integration. To investigate this hypothesis, we will use mouse transgenesis and virus-mediated gene transfer to induce RSPO2 and ZNRF3 gain- and loss-of-function in maturing adult-born neurons in vivo. Comprehensive comparative analysis of i) stage-specific neuronal marker expression, ii) the morphology of the axonal, dendritic, and synaptic compartment, and iii) the electrophysiological properties will provide insight into the function of the RSPO2/ZNRF3 pathway on neuronal maturation and integration. Moreover, we will use transcriptomic analyses to identify candidate targets and pathways that mediate the functional maturation and integration of adult-born neurons downstream of RSPO2/ZNRF3.Precise regulation of maturation of adult-born DG neurons is important for hippocampal information processing. We expect that this project will uncover new mechanistic principles underlying the control of maturation of adult-born hippocampal neurons thereby furthering our understanding of the regulation of hippocampal plasticity.