The human neocortex is the seat of many of the higher cognitive functions that make us human. These include our memory, speech and advanced learning. Our neocortex has greatly expanded during evolution, resulting in an increase in the number of nerve cells (neurons) within it, and an increase in overall size. This expansion was accompanied by folding of the cortical surface, which gives the brain its wrinkled appearance and allowed the expansion of the cortical surface area within the confinement of the developing skull. Despite their functional importance, we know relatively little about how these folds are formed in development. What is known, is that these cortical folds are very similar between individuals, so much so, that the largest folds are almost identical. This suggests that the formation of the correct number of folds in the correct location is important for their function. In fact, cognitive defects are observed in various neurodevelopmental disorders that result in abnormal cortical folding, i.e. disorders with too much folding, such as polymicrogyria, and not enough folding, such as lissencephaly, suggesting that the regulation of folding during development is crucial. My work has shown that the extracellular matrix (ECM), the proteins that surround cells in a tissue, has a key role in regulating how cortical folds form. Manipulating the ECM in tissue slices of human fetal neocortex kept in culture induced folding of the cortical plate. This ECM-induced folding was reduced or delayed in neocortex samples with specific neurodevelopmental defects, such as Down syndrome and prenatal methamphetamine exposure. Both of these disorders are known to have developmental delays or defects in the neocortex, which are currently not fully understood. The ECM-induced folding of human neocortex explants can now be used to probe these disorders and others. This is particularly important for the disorders that currently lack suitable animal models. Of these, the most relevant are the disorders that alter cortical folding, as many of the model systems used to study neocortex development naturally lack folding (such as mice). I predict that there are many more functions of ECM in human neocortex development, folding and related neurodevelopmental disorders. Therefore, the overall aim of my proposal is to investigate how ECM regulates human neocortex development and its related disorders, using the novel human neocortex explant systems I have developed. The first aim of my proposal is to use my ECM-folding assay to investigate the function of ECM genes that have already been linked to specific neurodevelopmental disorders in patients. Two candidates are the ECM protein perlecan, and the ECM receptor dystrogylcan. Both of these genes are linked to the folding disorder lissencehpaly. The second aim is to examine the exact composition of the ECM within the developing human neocortex. There is currently very little data on what ECM is expressed in the human neocortex, when it is expressed and where it is located. This is vital information that will help us understand not only the normal function of the ECM in human neocortex development, but also help understand and predict how mutations in ECM genes led to neurodevelopmental defects. The third aim is to test the function of ECM proteins in human neocortex development, using the human neocortex explant culture system and ECM-folding assay. This will increase our understanding of how ECM regulates the development and folding of the cortex, and its dysregulation. This fellowship funding would allow me to set up my independent research group, addressing these fundamental questions of how the human neocortex develops and how this development goes awry in developmental disorders. It will uncover the role of the ECM in both of these processes, and increase our knowledge and understanding of the normal neocortex development and folding, and the dysregulation seen in related disorders.