Researchers from the laboratory of Oscar Marín from the Centre for Developmental Neurobiology and the MRC Centre for Neurodevelopmental Disorders at King's College London in collaboration with the laboratory of Nenad Sestan at Yale School of Medicine have made a breakthrough in our understanding of GABAergic interneurons in the cortex, which may have profound implications for the treatment of several neurological disorders. The study, published in Science, provides evidence for the hypothesis that the functionality of GABAergic interneurons in the cerebral cortex is essentially "pre-determined" early during development by particular genes, rather than determined by interactions with other cortical regions later on in the developmental process.
The cerebral cortex is one of the most complex structure of the brain and is responsible for some of the brain's most sophisticated processes, from learning and memory to translating planned behaviours into physical actions. To achieve these functions, the cerebral cortex relies on a remarkable diversity of neurons. The cortex contains two main classes of neurons, pyramidal cells and interneurons. The latest group plays essential roles in the maintenance of neural network balance by shaping synchronised activity and controlling the function of pyramidal cells. The adult cortex contains 20 to 30 different classes of interneurons, each with very specific functions. Although the generation of different cortical interneuron cell types has been extensively studied over the past decades, it is still not clear when and how interneuron diversity comes about during brain development. One model proposes that interneurons acquire the potential to differentiate into a distinct subtype at the level of progenitors or shortly after becoming postmitotic while the competing model postulates that interneuron identity is established relatively late in development, after they have migrated to their final location, through interactions with the cortical environment.
Da Mi , leading author of the study said "This study dramatically increases our understanding of the mechanisms that generate interneuron diversity during brain development. The knowledge gained from this study will also inform the use of stem cell biology for the generation of distinct classes of human cortical interneurons for cell-based therapies in the future."
Oscar Marín and his colleagues have provided promising evidence for the hypothesis that the functional diversity of cortical interneurons is intrinsically determined by specific genetic programmes very shortly after interneurons are born. By analysing cortical interneurons in the mouse embryo across several developmental stages, the researchers were able to examine the gene expression patterns with single-cell resolution. This analysis revealed temporally and spatially restricted transcriptional patterns that indicate early cell type differentiation; in other words, GABAergic interneurons seem to be already committed to develop into a particular fate shortly after they are born (about half way through gestation). This study also demonstrates that generation of different classes of interneurons is regulated by the expression of specific genes early in development. Consequently, if future research is able to identify exactly which genes determine the functionality of which cells, perhaps cell-based therapies may represent a viable option for the treatment of a variety of neurological disorders that involve abnormalities in the cerebral cortex.
Oscar Marín commented: "It is very early days, but this means that we could use this information to generate very specific classes of cortical interneurons in the lab. Even from human cells. So, if we were to use cell therapy (transplanting neurons generated in the lab into the brain of living people) to treat some disorders (and this has been already tested in animal models, with the idea for example to tackle intractable epilepsy), we will need this type of information to 'engineer' the right kind of interneuron."
This work was supported by grants from the Wellcome Trust (103714MA) to Oscar Marin, the National Institute for Health (NS095654 and MH106934) to Nenad Sestan, and the Medical Research Council (N012291) and the Biotechnology and Biological Sciences Research Council (N006542) to David J Price and Thomas Pratt. Lynette Lim was supported by an EMBO postdoctoral fellowship. Oscar Marin is a Wellcome Trust Investigator.
Early emergence of cortical interneuron diversity in the mouse embryo
Da Mi, Zhen Li, Lynette Lim, Mingfeng Li, Monika Moissidis, Yifei Yang, Tianliuyun Gao, Tim Xiaoming Hu, Thomas Pratt, David J. Price, Nenad Sestan* & Oscar Marín*, Science