Role for ion conducting proteins in cortical malformation diseases

PROJECT SUMMARY Candidate. For my postdoctoral training, I transitioned from neurobiology-based methods in mouse sensory processing (PhD), to molecular and genetic approaches in human neurodevelopment. At present, a large gap exists in the field of functional neurogenomics, whereby clinically-derived genomic analysis is currently unable to be faithfully translated into functional data. My continued training with Dr. Christopher Walsh's research group will build into this research niche by supporting my development of new expertise in human genetics and single-cell approaches. Further, my long-term goal is to develop the broad skills needed to assess how genes that affect cellular excitability (e.g. channels, pumps, exchangers) can instruct neural circuit development; this complements well with my graduate training, where I developed expertise in the cellular basis of electrical signaling in olfactory and cerebellar neural circuits. In particular, my graduate studies cemented my expertise in neural systems physiology and single neuron contributions to circuit function, including whole-cell patch clamp electrophysiology, calcium imaging, optogenetics, chemogenetics, and in-vivo behavioral paradigms. The application of these skills to the area of human neurodevelopment will form the basis for developing my independent research program. Research. The idea that ion channels can disrupt cortex formation is a new area of study, particularly when exploring the mechanisms activated at a cellular level. Since dividing progenitor cells and newborn neurons in the developing cerebral cortex rely on ions for controlling cellular processes, I will test the new hypothesis that disrupted activity of specific ion fluxes is critical to cortex assembly. Proof of the existence of developmental channelopathies in the brain has remained elusive due to the heterogenous nature of cortical malformations and the fact that they are often are under extreme negative pressure evolutionarily. Given that I am describing and categorizing brain disorders that improve our understanding of disease mechanisms and the treatment of conditions related to malformation of cortical development (MCD), the significance of this work to human health is immediate as the results generated by this research will immediately improve genetic testing for diagnosed disorders. I will complete this research with a combination of both proven and innovative strategies, including: 1) sequencing analysis of non-consanguineous and consanguineous families to identify gene variants involved in brain malformations; 2) characterizing a novel mouse model for a developmental channelopathy; 3) development of a novel physiological assay in developing human cerebral organoids.