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

• Applicant: Professor Dr. Dieter Chichung Lie
• Subject Area: Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 270618364

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.

• DFG Programme: Research Grants