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

成年海马区的神经发生，即终生一代的海马齿状回颗粒(DG)神经元，对于依赖于海马的信息处理是至关重要的。目前的数据表明，成年海马神经发生的失调参与了老年认知障碍以及神经精神和退行性疾病的病理生理学。成年海马区神经发生的调控机制尚不完全清楚。这个项目的总体目标是破译控制成年出生的DG神经元功能成熟和整合的分子机制。我们最近的结果表明，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-连环蛋白途径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Wnt/β-catenin途径调节剂RSPO2沿苔藓纤维束(即DG神经元的轴突投射)表达。此外，我们还发现了RSPO2信号的靶标ZNRF3在发育中的成年神经元中表达的证据。本项目研究RSPO2/ZNRF3通路控制Wnt/β-catenin通路在成年出生的DG神经元中重新激活，从而调节其成熟和突触整合的假说。为了研究这一假说，我们将使用小鼠转基因和病毒介导的基因转移，在体内成熟的成年出生的神经元中诱导RSPO2和ZNRF3获得和功能丧失。综合比较分析RSPO2/ZNRF3通路在神经元成熟和整合过程中的作用：1)不同阶段神经元标志物的表达；2)轴突、树突和突触的形态；此外，我们将使用转录转录分析来确定介导RSPO2/ZNRF3下游成年出生神经元功能成熟和整合的候选靶点和途径。准确调控成年出生DG神经元的成熟对于海马信息处理非常重要。我们期望这个项目将揭示控制成年出生的海马神经元成熟的新的机制原理，从而进一步加深我们对海马可塑性调节的理解。

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.