Functional characterization of neurotransmitter-mediated signaling in human neocortical development

• Applicant: Dr. Simone Mayer
• Subject Area: Developmental Neurobiology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324874657

In evolutionary terms, the neocortex is the newest part of the mammalian brain and is the source of the complex cognitive skills of mammals. While the genome has been relatively stable, the neocortex has expanded significantly in the primate lineage. Both the number of cells and the number of different cell types in the neocortex has increased during the evolution of the human brain. The question therefore arises how the increased production of cells and the differentiation of different cell types is achieved during neocortical development. Previous research has shown that an enlarged repertoire of neural progenitor types underlies the generation of the larger number of neurons and glia that constitute the mature neocortex. However, how these neural progenitor cells maintain their proliferative potential throughout the extended neurogenic period in humans and how the large diversity of cell types is generated remains unknown. Studies in rodents have shown that neurotransmitter-mediated signaling in the developing brain regulates both the proliferation of neural progenitor cells and the differentiation of newborn neurons. We hypothesize that neurotransmitter-mediated intercellular signaling plays an even more important role in the development of the complex human brain. We therefore aim to study how the different neural progenitor cell types in the human brain are regulated by neurotransmitters. We will use changes in the concentration of intracellular calcium as a readout of the responsiveness of a cell to different neurotransmitters, since calcium is an important second messenger that links intercellular signaling to changes in transcription and thereby can alter cell fates. In Objective 1 we will characterize the physiological response profiles of human neural progenitor cells and newborn neurons to a range of different neurotransmitters. In Objective 2, we will use a novel high-throughput approach to link the physiological response profiles to cell types and states by analyzing single-cell transcriptomes. In Objective 3, we will study the long-term effects of neurotransmitter signaling on the proliferation and differentiation of different cell types by analyzing transcriptomes of single cells after neurotransmitter application and by studying changes in proliferation in tissue slices. This systems biology approach will allow us for the first time to elucidate how different cell types in the developing human neocortex regulate each other through neurotransmitter-mediated signaling. Since many neurodevelopmental disorders, such as autism spectrum disorders, are caused by mutations in genes that encode synaptic proteins, this research is instrumental for understanding how these mutations affect brain development even prior to the formation of synapses.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Arnold Kriegstein, Ph.D.