Fellowship summary by Dr. Rumbaugh

ANALYSIS OF NEURONAL FUNCTION FROM HUMAN NEURONS DERIVED FROM IPSC LINES WITH DIFFERING LEVELS OF SYNGAP1 GENETIC PATHOGENICITY

The overarching goal of this fellowship is to train a postdoctoral fellow, over the course of three years, to study neurons derived from a series of distinct human induced pluripotent stem cell (hiPSC) lines harboring disruptive SYNGAP1 variants. The Trainee will acquire specific expertise in neurobiology and disease modeling methodologies, including human stem cells and ethics related to their use, for hypothesis-driven research. The hypothesis for this project is that the pathogenicity of distinct SYNGAP1 variants found in patients will correlate with the extent of dysfunction in neurons derived from their own cells. To test this idea, the trainee will perform sophisticated neurophysiological and morphological analysis on neurons derived from three distinct hiPSC lines. Each hiPSC line will have a distinct SYNGAP1 variant, with the distinct mutations predicted to cause different effects on SynGAP protein levels in human neurons (Line 1= ~100% loss of protein, Line 2= 50% loss of protein, Line 3 = ~25% loss of protein). We expect to find clear neurophysiological and morphological deficits in human neurons lacking SynGAP protein (Line 1). These phenotypes are expected to be less severe in the other two lines, especially in Line 3, which harbors a splice mutation predicted to only moderately impact SynGAP protein levels. Such results would be impactful because the clinical phenotype of the patient that the donated cells used to make Line 3 is milder than what is normally seen in patients with pathogenic SYNGAP1 variants. Thus, the trainee is likely to discover cellular biomarkers that predict the severity of clinical phenotypes commonly observed in SYNGAP1 patients. These cellular biomarkers will be used to guide ongoing drug discovery efforts for SYNGAP1-related brain disorders. Specifically, drug candidates that improve cellular phenotypes common to patient-derived neuronal models would be given the highest priority for further development.