Key Points:
- CURE Epilepsy Taking Flight Award grantee Dr. Lakshmi Subramanian is working to uncover the underlying causes of focal cortical dysplasia (FCD), a severe childhood epilepsy syndrome characterized by developmental malformations in the part of the brain known as the cortex.
- Dr. Subramanian found that disrupting the mTOR signaling pathway caused a series of biological changes that may explain how FCD arises.
- Understanding these changes could help researchers identify newer, more effective, and less invasive therapeutic options than those currently available.
Deep Dive:
During development in the womb, the human brain undergoes a substantial expansion in size, particularly in the outermost part known as the cortex [1]. During this time, brain cells grow and divide rapidly, normally organizing themselves into layers. As the brain develops, an orderly arrangement of cells is created, in part, by the shape, position, and movement of outer radial glia (oRG) cells. These cells give rise to newborn nerve cells in the human brain and also form the scaffold that the immature nerve cells use to navigate to their correct location, mature, and connect normally [3]. In focal cortical dysplasia (FCD), however, brain cells fail to organize properly, leading to focal lesions and usually intractable epilepsy [2]. Surgery is often the only effective treatment option.
The mTOR pathway is known to be active in human oRG cells during development [4], but the function of this pathway in these cells is unknown. Taking Flight Award grantee Dr. Lakshmi Subramanian, while working in the laboratory of Dr. Arnold Kriegstein at University of California San Francisco, sought to determine the specific role of the mTOR pathway in the development of FCD [5].
Dr. Subramanian and colleagues first successfully established simplified models of the developing human cortex in order to manipulate mTOR signals and evaluate the resulting effects on oRG cells. They activated or blocked mTOR signals in two different human tissue-based models and found that sustained mTOR signals were required to maintain oRG cell shape and structure. Specifically, when mTOR signals were disrupted, oRG cells lost their typically elongated shape, shortened significantly, and lost their ability to “move” normally in the developing brain. As a result, the scaffold along which nerve cells migrate, mature, and connect was also disrupted, providing a mechanism for how abnormal brain organization may arise in FCD.
In future research, Dr. Subramanian hopes these human brain model systems can be used to investigate how displaced, misshapen oRG cells affect long-term changes in the brain. More information about how oRG cells use mTOR signals may help identify additional components of the pathway that can be investigated as potential therapies or diagnostics. An advanced understanding of this pathway may allow for development of less invasive approaches to treating FCD and other mTOR-mediated developmental epilepsies. These proteins could conceivably be targeted to develop new diagnostics and treatments other than invasive surgery for patients with FCD and other mTOR-mediated developmental epilepsies.
Dr. Lakshmi Subramanian is a CURE Epilepsy Taking Flight Award grantee and NARSAD Young Investigator, Neuroscience/Stem Cell Biology Research at Broad Center for Regeneration Medicine, University of California San Francisco.
Literature Cited
[1] Hatten, M.E. Central nervous system neuronal migration. Annu. Rev. Neurosci. 1999; 22: 511-539.
[2] Iffland, P.H. and Crino, P.B. Focal cortical dysplasia: gene mutations, cell signaling, and therapeutic implications. Annu. Rev. Pathol. 2017; 12: 547-571.
[3] Ostrem, B., Di Lullo, E., and Kriegstein, A.R. oRGs and mitotic somal translocation – a role in development and disease. Curr. Opin. Neurobiol. 2017; 42: 61-67.
[4] Pollen, A.A., Bhaduri, A., Andrews, M. et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell 2019; 176(4): 743-756.
[5] Andrews, M.G., Subramanian, K., and Kriegstein, A.R. mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex. eLife 2020; 9: e58737.