Perturbations in the development of the cerebral cortex underlie a wide array of common neurogenic syndromes, ranging from dyslexia to cerebral palsy. The goal of the proposed research is to elucidate mechanisms by which improper formation of the cortex occurs, and ultimately discover novel targets to treat patients. Here we use next-generation sequencing to isolate genes involved in cortical malformations complemented with an in vitro model in which we can experimentally determine pathways leading to aberrant phenotypes. For this, we will use human induced pluripotent stem cells (hiPSC) to recapitulate the development of human cerebral cortex in vitro. Importantly, in this in vitro cerebral model we will study neuronal activity, a key biomarker and essential contributor to neural circuit development. Further, using hiPSCs derived from individuals with cortical malformations, we can study aberrant neurodevelopmental features along a range of time points during embryonic development. Wide-field fluorescence imaging will enable the analysis of large populations of neurons, which can be probed in real-time with targeted pharmacological agents and stimulation paradigms. The proposed work will have immediate health benefits; the discovery of genes involved in disease can be promptly used to screen children with undiagnosed disorders. Additionally, using neuronal activity as a biomarker, we plan to develop this novel tool for isolating new mechanisms of cortical malformation.
Malformations in cortical development can lead to profoundly deleterious syndromes in countless children worldwide with genetic afflictions that have yet to be described. By studying patients with severe neurological symptoms and abnormal brain structure, we can better understand the mechanisms by which human cerebral cortex development can go wrong, and ultimately treat affected patients. Additionally, the goal of the White House's ?Precision Medicine Initiative? is to enable health care providers to tailor treatment and prevention strategies to people's unique characteristics, including their genome sequences. Currently, gene variants implicated in the genomes of individuals with brain malformations return with unknown function. Our goal is to elaborate pathogenic variants and develop an accurate annotated genes variants list for tailored diagnostic and personalized medicine.