Functional characterization of neurotransmitter-mediated signaling in human neocortical development
Final Report Abstract
The human neocortex is the brain area responsible for many different functions including, processing of sensory information, language, and cognition. The neocortex of humans is composed of many more cells than that for example of the mouse, a model organism used frequently in biomedical research. It is therefore a great evolutionary and medical interest to understand the cellular and molecular mechanisms that drive the development of our enlarged neocortex and thus give rise to our complex cognitive traits. Previous work on rodents has demonstrated that neurotransmitter signaling occurs already at earliest stages of brain development - even before synapses are formed - when stem and progenitor cells divide to generate neurons. In our study, we have for the first time to our knowledge performed calcium imaging in primary human neocortical tissue during the second trimester of gestation. We found responses to diverse neurotransmitters starting at the end of the first trimester of gestation. We developed a new approach that allowed us to link the recorded calcium responses to the molecular cell identity through a technique called “single-cell RNA-sequencing”. This method allowed us to identify that responses to neurotransmitter stimulation were already specific to cell types and even cell states at these early developmental stages. These findings have several implications. The high specificity of early neurotransmitter signaling implies a functional importance for brain development and possibly also brain evolution. Moreover, any dysregulation might lead to disease. For example, mutations in neurotransmitter receptors have been reported in brain malformations and many drugs, such as anti-epileptics and anti-depressants target neurotransmitter systems thus potentially interfering with fetal brain development if administered during pregnancy.
Publications
- Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature, 2018 Mar 15; 555(7696):377-381
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang E, Gutierrez Martin AJ, Kriegstein AJ, Mathern GW, Oldham M, Huang EJ, Garcia- Verdugo JM, Yang Z, Alvarez-Buylla A
(See online at https://doi.org/10.1038/nature25975) - Multimodal single-cell analysis reveals physiological maturation in the developing human neocortex. Neuron, 2019 Apr 3;102(1):143-158
Mayer S, Chen J, Velmeshev D, Mayer, A, Eze U, Paredes MF, Alvarado B, Wang S, Cunha CE, Lovegren N, Gonzales ML, Szpankowski, L, Leyrat, A,West, JAA, Alvarez-Buylla A, Nowakowski TJ, Pollen AA, Kriegstein AR
(See online at https://doi.org/10.1016/j.neuron.2019.01.027) - Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature. 2019 Jul 17
Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, Vistnes S, Stockley JH, Young A, Steindel M, Tung B, Goyal N, Bhaduri A, Mayer S, Engler JB, Bayraktar OA, Franklin RJM, Haeussler M, Reynolds R, Schafer DP, Friese MA, Shiow LR, Kriegstein AR, Rowitch DH
(See online at https://doi.org/10.1038/s41586-019-1404-z) - Single-Cell Genomics Identifies Cell Type-Specific Molecular Changes in Autism. Science, 2019 May 17;364(6441):685-689
Velmeshev D, Schirmer L, Jung D, Haeussler M, Perez Y, Mayer S, Bhaduri A, Goyal N, Rowitch DH, Kriegstein AR
(See online at https://doi.org/10.1126/science.aav8130)
